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f.C  BERKELEY 

BIOLOGY  LIBRARY  UCB 


.-.-".'      '     '   '    ,.    '.    '.  .    .EXCHANGE 

6   1922 


THE  ADAPTIVE  CHANGES  OF 
HEART  MUSCLE 

-by-- 

WILLIAM  DEAN  COLLIER,  A.  B.,  A.  M. 


SUBMITTED  IN  PARTIAL  FULFILMENT- OF 

THE  REQUIREMENTS  FOR  THE 

DEGREE  OF  DOCTOR  OF 

PHILOSOPHY 

— in  the — 


GRADUATE  SCHOOL 


—of  the— 


UNIVERSITY  OF  MISSOURI 
1922 


THE  ADAPTIVE  CHANGES  OF  HEART  MUSCLE  * 

WILLIAM  DEAN  COLLIER 
(From  the  Laboratory  of  Pathology  of  the  University  of  Missouri.} 

SYNOPSIS 

INTRODUCTION. 

The  basis  of  comparative  analysis. 

The  identification  of  the  metabiotic  fiber. 

The  changes  of  excitation. 

The  changes  of  depression. 

The  changes  of  depression  superimposed  upon  excitation. 

THE   FUNCTIONAL  HYPERTROPHY,  AN   ANABIOTIC   ADAPTATION. 

Data  of  experimental  production. 

The  nature  and  significance  of  the  functional  hypertrophy. 
The  pathological  conception  of  hypertrophy. 
Identity  of  hypertrophy  and  degeneration. 
A  compensatory  sequel  to  some  pathological  lesion. 
The  physiological  conception  of  hypertrophy. 
The  mechanism  of  the  organic  relationships  involved  in  hypertrophy  of  the 

heart. 

The  cellular  mechanics  of  hypertrophy. 
KATABIOTIC  ADAPTIVE  PROCESSES. 
Experimental  data. 

Mechanics  of  katabiosis  from  overexcitation. 
Mechanics  of  katabiosis  from  depression. 
Mechanics  of  anabiosis  from  excitation  following  depression. 
Mechanics  of  katabiosis  from  depression  following  excitation. 
ANALYSIS  OF  THE  ACTION  OF  STIMULI. 
Non-specificity  of  stimuli. 

THE  PATHOLOGICAL  SIGNIFICANCE   OF   THE   CHANGES. 

Dilatation. 

Vacuolar  degeneration. 

Hyaline  degeneration. 

Cloudy  swelling. 

Necrosis,  necrobiosis,  atrophy. 

Intercalated  discs. 

Segmentation  and  fragmentation. 

Introduction.  —  The  adaptive  changes  in  the  heart  muscle 
are  to  be  understood  as  the  physiological  and  anatomical 
changes  in  its  vital  phenomena  in  response  to  changes  in  its 

*  The  substance  of  an  Inaugural  Dissertation  for  the  Degree  of  Doctor  of 
Philosophy  at  the  University  of  Missouri.  Received  for  publication  March  10, 

1922. 

207 


2oS  " :  \ . . : ; ' ;  COLLIER 

environment.  Such  changes  in  environment  are,  by  definition, 
stimuli  (Verworn,  '96).  It  is  deduced  from  the  work  of  Ver- 
worn  ('13,  77)  and  Dolley  ('22)  that  the  primary  effect  of  the 
stimulus  upon  the  cell  is  always  quantitative,  though  stimuli 
are  both  quantitative  and  qualitative.  This  is  true  for  the 
effect  of  the  stimulus  in  the  functioning  cell  because  of  its 
specific  differentiation  which  allows  of  only  one  functional 
product  or  capacity.  That  is,  the  muscle  cell  can  only  con- 
tract and  the  gland  cell  can  only  secrete  its  specific  product. 
However,  this  one  specific  product  or  capacity  may  be  the 
response  to  stimuli  of  different  quality,  namely,  nervous, 
thermic,  mechanical,  chemical,  or  to  a  single  quality  of  stimu- 
lus in  different  quantitative  degrees,  with  the  result  that  the 
intensity  of  the  production  of  the  specific  product  varies  over 
a  very  wide  range. 

All  such  changes  in  the  vital  processes  of  the  cell  due  to  ex- 
ternal conditions  are  the  manifestations  of  its  property  of  irri- 
tability. Irritability  displays  itself  by  two  processes,  excita- 
tion and  depression.  Excitation  is  characterized  by  increased 
response  of  the  specific  mechanism,  depression  by  decreased 
response,  depending  upon  the  intensity,  duration,  and  kind  of 
stimulation.  Consequently,  the  study  of  the  adaptive  changes 
in  heart  muscle  is  synonymous  with  the  study  of  the  reactions 
of  the  cell  to  stimulation  and  of  the  manifestations  of  the  irri- 
tability of  the  cell. 

The  basis  of  comparative  analysis.  —  The  preliminary  in- 
spection of  the  fibers  showed  a  great  difference  in  the  functional 
morphology  between  the  fibers  within  the  same  animal  and 
more  strikingly  a  greater  difference  between  the  fibers  in  dif- 
ferent individuals  of  the  same  species.  Therefore,  unless  there 
is  a  fixed  standard  of  comparison,  a  constant  morphological 
criterion  as  in  the  nerve  cell,  characterizing  the  species,  no 
exact  comparison  or  analysis  could  be  made. 

The  comparison  of  fiber  with  fiber,  of  group  of  fibers  with 
group  of  fibers,  and  of  animal  of  the  species  with  animal  of  the 
species  is  based  upon  two  criteria.  The  first  of  these  is  the 
constancy  of  the  morphological  picture  of  the  heart  muscle 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE  2OQ 

fiber  in  metabolic  nucleo-cytoplasmic  equilibrium  which  con- 
trasts it  with  all  changes  characteristic  of  excitation  or  depres- 
sion. The  second  is  the  constancy  of  the  numerical  coefficient 
of  the  nucleus-plasma  relation,  which  holds  as  a  numerical  law 
for  the  resting  cell  norm  of  the  species  (Dolley,  '14).  This 
numerical  coefficient  is  the  quotient  obtained  by  dividing  the 
figure  representing  the  size  of  the  cytoplasm  alone  by  the  size 
figure  of  the  nucleus. 

First,  there  will  be  defined  what  is  meant  by  metabolic 
nucleo-cytoplasmic  equilibrium.  The  term  is  used  to  designate 
the  state  in  which  there  is  no  evidence  of  any  embarrassment 
of  the  cell  demonstrable  morphologically  or  by  a  change  from 
the  normal  nucleo-cytoplasmic  coefficient.  The  numerical  co- 
efficient is  the  index  of  the  reciprocal  interchange  of  nuclear 
and  cytoplasmic  materials  and  consequently  of  cell  metabo- 
lism. If  the  fiber  is  embarrassed  by  overexcitation,  it  is  shown 
by  the  tables  that  the  upset  of  this  relation  is  in  favor  of  the 
cytoplasm,  —  the  coefficient  becomes  a  larger  figure  than  the 
norm;  if  the  embarrassment  is  effected  by  depression,  the  upset 
is  in  favor  of  the  nucleus, —  the  coefficient  becomes  a  smaller 
figure.  From  the  standpoint  of  the  nucleus-plasma  relation, 
the  constancy  of  morphology  and  the  constancy  of  the  nucleus- 
plasma  coefficient  represent  obviously  the  state  in  which  the 
physico-chemical  factors  of  anabolism  and  katabolism  are  in 
a  state  of  equilibrium.  To  express  this  state  of  metabolic 
nucleo-cytoplasmic  equilibrium  of  the  muscle  fiber,  the  term 
metabiotic  fiber  will  be  used.  It  is  used  because  it  expresses  the 
balanced  "way  of  life"  of  the  normally  functioning  fiber. 

The  term  metabiotic  is  also  convenient  because  its  root  word 
permits  the  opposite  variations  of  the  metabolism  of  stimula- 
tion to  be  contrasted.  A  katabiotic  fiber  is  one  in  which  through 
either  excitation  or  depression,  the  disintegrative  processes  pre- 
dominate. An  anabiotic  fiber  expresses  one  in  a  progressive 
process  of  upbuilding,  such  as  the  functional  hypertrophy 
which  results  from  regulated  excitation. 

The  morphological  identification  of  the  metabiotic  fiber.  — 
In  the  metabiotic  fiber,  the  nuclear  membrane  is  regular  and 


210  COLLIER 

shows  no  indentations,  bulges,  or  wrinkles.  The  shape  of  the 
nucleus  in  longitudinal  section  is  almost  rectangular  with  its 
length  about  four  times  as  long  as  the  width  (rat  heart),  al- 
though the  ends  are  bluntly  rounded.  The  ground  substance 
of  the  nucleus  stains  with  equal  intensity  and  the  chromatin 
network  is  regularly  distributed  over  the  whole  area  in  thin 
filaments  with  small  knots  of  chromatin  at  the  nodal  points. 
There  is  usually  but  one  karyosome  present.  The  cytoplasm 
has  a  distinctness  which  is  unequalled  in  any  other  stage  of  the 
functional  process.  The  sarcoplasm  and  the  fibrillae  stain  uni- 
formly throughout  the  fiber  and  show  no  evidence  of  edema  or 
disintegration  of  the  normal  elements  of  the  fiber.  In  conclu- 
sion, it  can  be  said  that  the  intensity  of  the  staining  of  the 
nucleus  and  cytoplasm  is  uniform,  which  suggests  a  state  free 
from  embarrassment,  while  between  them  there  is  a  relative  in- 
tensity of  staining  whose  constancy  suggests  an  equilibrium  in 
their  state  of  interdependency. 

In  the  case  of  either  overexcitation  or  depression  of  the 
fibers,  this  relative  intensity  of  stain  does  not  hold. 

The  changes  of  excitation.  —  The  earliest  change  in  the  in- 
dividual fiber  to  overexcitation  is  a  stage  of  hyper  chroma  tism 
of  the  nucleus  and  an  increase  in  the  cross  sectional  area  of  the 
fiber  and  its  nucleus.  This  increase  in  size  is  exactly  propor- 
tionate between  fiber  and  nucleus  so  that  the  metabolic  rela- 
tionship of  the  metabiotic  fiber  is  retained  in  the  first  stage  of 
excitation.  Dolley  has  found  an  identical  hypertrophy  and 
hyperchromatism  in  the  initial  stage  of  excitation  in  both  the 
nerve  cell  ('09,  '13)  and  gland  cell  (unpublished  work).  Not 
only  is  there  an  identity  of  the  nucleus-plasma  coefficient  but 
also  the  morphological  picture  is  qualitatively  identical,  that 
is,  both  the  structural  elements  and  the  proportionate  relation- 
ship of  the  elements  are  identical.  For  this  reason,  there  was 
no  discrimination  between  these  two  stages,  the  less  hyper- 
chromatic  stage  and  the  more  hyperchromatic  stage  of  initial 
excitation,  in  the  selection  of  metabiotic  fibers  for  measure- 
ment. As  Dolley  has  pointed  out  for  the  nerve  cell,  the  relation 
of  this  stage  to  the  metabiotic  (resting  cell)  fiber  duplicates  the 


ADAPTIVE  CHANGES   OF  HEART  MUSCLE  211 

relationship  of  the  functionally  hypertrophied  fiber  to  the  non- 
hyper  trophied  fiber.  Function  gives  the  same  relationship  as 
growth.  The  identity  of  the  nucleus-plasma  relationship  and 
the  qualitative  morphological  identity  of  the  states  indicates 
that  the  proportionate  increase  in  size  of  both  nucleus  and 
cytoplasm  in  both  immediate  function  and  the  resultant  func- 
tional growth  is  the  expression  of  a  relatively  greater  rate  of 
metabolism.  The  increased  intensity  of  stimulation  has  in- 
creased the  rate  of  this  definitely  proportionate  reciprocal 
interchange. 

The  next  change  observed  is  a  shrinkage  of  both  the  cross 
sectional  area  of  the  fiber  and  of  the  nucleus,  but  a  greater 
shrinkage  of  the  nucleus  with  a  shift  of  the  nucleus-plasma 
relation  in  favor  of  the  cytoplasm.  The  nucleus  remains 
hyper  chroma  tic.  This  shrunken  stage  of  the  nucleus  is  also 
often  associated  with  beginning  edema  of  the  sarcoplasm. 
This  change  in  heart  muscle  is  identical  both  in  form 
and  in  its  place  in  the  process  with  the  Hodge  type  of 
nerve  cell. 

The  next  change  is  the  initial  edema  of  the  nucleus  and  the 
progressive  edema  of  the  cytoplasm.  The  subsequent  adapta- 
tions to  overexcitation  are  those  of  progressive  edema  of  both 
the  nucleus  and  cytoplasm  with  their  consequent  increase  in 
size,  with  the  exception  of  the  final  stage.  The  cytoplasm  in- 
creases relatively  more,  so  that  there  is  a  shift  of  the  nucleus- 
plasma  coefficient  in  favor  of  the  cytoplasm.  Coincident  with 
the  progressive  edema,  there  is  a  progressive  loss  of  chromatic 
material  from  the  nucleus  and  from  the  cross  striations.  The 
edema  and  loss  of  chromatic  material  give  objective  expression 
to  the  shift  of  the  nucleus-plasma  coefficient  in  favor  of  the 
cytoplasm. 

The  final  stage  is  a  shrinkage  of  both  the  cross  sectional  area 
and  of  the  nucleus.  This  is  associated  with  a  complete  loss  of 
chromatic  material  from  the  fiber  and  nucleus  with  the  excep- 
tion of  the  chromatic  material  within  the  karyosome.  The 
striations  are  gone  and  are  replaced  by  a  foam  structure,  prob- 
ably the  effect  of  vacuolization.  The  nuclear  shrinkage  be- 
comes again  relatively  greater.  The  process  was  thus  followed 


212  COLLIER 

almost  to  complete  organic  exhaustion,  with  its  final  dechro- 
matization  of  the  nucleus.  It  corresponds  in  complete  detail 
with  the  process  of  excitation  in  nerve  and  gland  cells  (Dolley). 

Soon  after  the  karyolysis  of  the  nucleus  becomes  pronounced, 
certain  changes  begin  at  the  ends  of  the  nucleus.  Up  to  this 
time,  the  longitudinal  fibrillae  (muscle  columns)  have  seemed 
to  be  contiguous  with  the  nuclear  membrane,  but  at  this  time 
the  cross  striations  at  the  ends  of  the  nucleus  begin  to  be  dis- 
organized. Instead  of  forming  a  continuous  line  across  the 
fiber,  the  striations  disintegrate  and  form  a  row  of  globules 
which  retain  the  position  formerly  occupied  by  the  cross  stria- 
tions. Later,  the  smaller  individual  globules  fuse  to  form 
larger  globules.  This  probably  indicates  the  disorganization 
of  the  entire  sarcomere  with  the  fusion  of  the  smaller  globules 
into  larger  ones  as  the  confines  of  the  sarcomere  degenerate. 
It  seems  to  be  one  bit  of  evidence  in  favor  of  the  view  that  the 
sarcomere  has  four  walls  which  is  still  a  theory  to  be  demon- 
strated morphologically.  The  change  in  structure  is  accom- 
panied by  a  change  in  the  affinity  for  stains.  As  the  striations 
change  in  form,  they  progressively  lose  their  affinity  for  the 
basic  stain  and  gain  in  intensity  for  acid  stain. 

This  disintegration  makes  much  more  rapid  progress  in  the 
direction  of  the  length  of  the  fiber  than  in  its  breadth.  In  fact, 
it  may  be  so  nearly  confined  to  the  center  of  the  fiber  that  it 
seems  that  the  section  has  undergone  longitudinal  splitting.  It 
is  this  phenomenon,  undoubtedly,  that  Wilks  and  Rindfleisch 
(cited  by  Goldenberg,  '86,  88)  thought  was  a  true  longitudinal 
splitting  that  would  explain  the  mechanics  of  the  produc- 
tion of  heart  hypertrophy.  After  the  longitudinal  splitting 
is  well  started,  the  disorganization  spreads  out  in  a  radial 
direction  from  the  nucleus  as  the  center  until  the  whole  fiber 
has  lost  any  evidence  of  cross  striations  and  has  few  remaining 
fragments  of  the  longitudinal  nbrillae.  It  can  be  said  for  the 
rat  and  for  the  dog  that  the  often  mentioned  ' '  areas  of  undif- 
ferentiated  protoplasm  "  at  the  ends  of  the  nuclei  are  character- 
istic of  an  embarrassment  of  the  fiber  from  excitation  when 
they  are  of  sufficient  size  to  be  recognized,  and  are  never  found 
in  the  metabiotic  fiber  or  in  the  depressed  fiber  which  is 


ADAPTIVE  CHANGES  OF  HEART  MUSCLE        213 

uncomplicated  by  an  initial  excitation.  Theoretically,  there  is 
a  small  cone  of  sarcoplasm  at  each  end  of  the  nucleus  which 
does  not  contain  fibrillae  since  the  conception  that  the  fibrillae 
course  around  the  nucleus  predicates  the  formation  of  such  a 
cone.  This  cone  becomes  much  enlarged  and  becomes  demon- 
strable in  the  later  stages  of  excitation,  in  which  case  the  in- 
creased metabolic  activity  is  associated  with  the  using  up  of 
cell  substance  and  consequent  katabiotic  changes  around  the 
nucleus. 

The  changes  of  depression.  —  The  earliest  change  of  depres- 
sion is  a  shrinkage  of  the  fiber  and  an  absolute  as  well  as  relative 
increase  in  the  size  of  the  nucleus  and  in  the  nuclear  materials. 
This  stage  of  depression  is  best  distinguished  by  its  character- 
istic nuclear  changes.  The  contour  of  the  nucleus  is  well 
rounded  but  shows  localized  bulgings  from  its  sides,  usually 
in  areas  where  the  chromatin  is  most  dense.  The  chromatin 
network  is  heavier  and  has  larger  and  more  numerous  knots  of 
chromatin  at  the  junction  of  its  meshes.  The  distension  of  the 
nuclear  membrane  inclosing  an  excess  amount  of  stored  chro- 
matin demonstrates  that  chromatin  is  being  made  faster  than 
it  is  being  discharged.  The  considerable  shift  in  the  nucleus- 
plasma  relation  and  the  coincident  increase  in  the  absolute  size 
of  the  nucleus  demonstrate  the  shift  of  the  reciprocal  inter- 
change of  substance  in  favor  of  the  nucleus.  This  evidence 
indicates  that  the  cytoplasm  is  progressively  unable  to  with- 
draw substances  from  the  nucleus,  but  that  nuclear  syntheses 
continue  for  a  time,  from  substances  elaborated  by  the  cyto- 
plasm before  the  onset  of  depression.  Eventually,  the  cyto- 
plasm fails  completely  to  give  or  take  substances  from  the 
nucleus  and  becomes  degenerated,  as  will  appear. 

In  the  cytoplasm,  the  materials  are  condensed  so  that 
Cohnheim's  areas  are  rarely  found  in  fibers  cut  in  cross  section. 
This  contrasts  the  condensation  of  depression  with  the  edema 
of  excitation,  as  the  latter  conditions  the  formation  of  Cohn- 
heim's areas  in  direct  proportion  to  the  degree  of  edema.  The 
condensation  is  accompanied  by  a  considerable  increase  in  the 
intensity  of  the  staining  reactions  of  the  cytoplasm.  The 


214  COLLIER 

eosinophilic  reaction  as  well  as  the  chromatic  reaction  are 
increased,  but  the  chromatic  is  predominant  as  shown  by  a 
faint  violet  tinge  to  the  whole  fiber  as  well  as  a  much  heavier 
staining  of  the  cross  striations.  Whether  the  stria tions  actu- 
ally increase  in  volume  cannot  be  stated,  although  their  width 
and  intensity  of  stain  is  apparently  increased.  This  may  be 
due  to  a  simple  condensation  of  the  cross  striations  into  a 
smaller  cross  sectional  area. 

This  hyperchromatic  depressed  fiber  can  be  distinguished 
from  the  hyperchromatic  Hodge  stage  of  excitation  by  the 
observation  that  the  microscopical  field  containing  Hodge 
fibers  also  contains  a  number  of  fibers  in  more  advanced  exci- 
tation. Also,  the  Hodge  cell  has  a  shrunken  nucleus  while  this 
type  of  depressed  nucleus  is  relatively  and  absolutely  increased 
in  size  and  has  a  tendency  to  bulge.  This  type  of  irregularity 
of  the  nuclear  membrane,  the  shift  of  the  nucleus-plasma  rela- 
tionship, and  the  marked  intensity  of  the  staining  reactions 
differentiate  the  depressed  from  the  metabiotic  and  the  Hodge 
fiber. 

The  second  nuclear  change  in  depression  is  a  shrinkage  of  the 
nucleus  in  its  short  diameter  and  a  coincident  increase  in  its 
length.  This  is  consecutive  to  the  same  change  in  the  fiber. 
This  type  of  hyperchromatic  nucleus  is  not  so  easily  distin- 
guished from  the  Hodge  nucleus.  Eosinophilia  now  becomes 
predominant  in  the  cytoplasm  and  thus  conforms  to  all  de- 
pressions. The  eosinophilia  coupled  with  the  changed  form  of 
the  nucleus  is  sufficient,  however,  to  differentiate  this  stage  of 
depression  from  the  Hodge  fiber  which  is  not  eosinophilous 
and  may  even  be  edema tous. 

The  characteristic  changes  of  more  advanced  depression  are 
the  progressive  shrinkage  of  both  the  cytoplasm  and  the 
nucleus  and  the  progressive  eosinophilia  and  regressive  baso- 
philic  reactions  which  approach  a  hyaline  condition  of  the 
fiber. 

Changes  of  depression  superimposed  upon  excitation.  — 
While  excitation  and  depression  are  found  in  pure  states  and 
are  discussed  as  distinctly  opposite  phases  of  the  same  process, 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE  215 

they  are  often  found  superimposed  one  upon  the  other.  It 
will  be  shown  later  that  a  single  drug  has  the  capability  of 
acting  as  an  initial  excitant  and  a  later  depressant  if  the  size 
of  the  dose  or  the  duration  of  its  administration  is  of  a  sufficient 
degree.  It  is  evident,  then,  that  it  is  possible  to  have  a  de- 
pressant effect  superimposed  upon  an  excitant  effect  by  the 
continued  administration  of  a  single  drug  or  by  superimposing 
a  depressant  degree  of  any  kind  of  stimulus  upon  an  excitant 
degree  of  any  stimulus. 

Fibers  have  been  put  under  conditions  which  were  known  to 
incite  the  changes  of  excitation  and  then  the  same  fibers  were 
put  under  conditions  which  were  known  to  incite  the  changes 
of  depression.  The  resulting  morphological  picture  is  a  com- 
plex of  the  morphological  changes  associated  with  excitation 
and  with  depression.  They  show  deeply  stained  nuclei  packed 
with  chroma  tin  and  supernumerary  karyosomes,  but  the  cyto- 
plasm shows  the  depth  of  staining  and  condensation  character- 
istic of  depression,  along  with  the  globulation  of  cross  striations 
and  sarcomeres  and  the  longitudinal  splitting  which  are  char- 
acteristics of  the  later  stages  of  excitation. 

Such  a  morphological  complex  is  not  found  after  superim- 
posing excitation  upon  depression.  It  will  be  shown  that  the 
conditioning  of  excitation  removes  the  restraint  imposed  by 
depression  gradually,  with  less  and  less  degrees  of  depression 
under  the  continued  influence  of  the  excitant  conditions,  until 
the  morphological  picture  attains  the  state  of  the  metabiotic 
fiber.  It  brings  the  fibers  back  to  normal.  Further  condition- 
ing of  excitation  simply  carries  the  fiber  through  the  same 
changes  as  any  fiber  not  in  depression. 

In  conclusion,  a  very  important  statement  should  be  made, 
namely,  that  in  all  fibers,  regardless  of  the  degree  of  structural 
change  induced  by  overexcitation  or  by  depression,  if  there 
were  any  remaining  cross  striations,  these  striations  were 
caught  in  all  the  different  stages  of  contraction  and  relaxation. 

Therefore,  it  is  well  established  that  there  is  a  state  of  meta- 
bolic equilibrium,  a  metabiotic  state,  of  heart  muscle  which 
can  be  differentiated  morphologically  from  all  other  states  of 


2l6  COLLIER 

heart  muscle  in  either  overexcitation  or  depression.  Twenty- 
five  of  these  fibers  in  cross  section  from  each  animal  were 
drawn  by  the  aid  of  the  camera  lucida,  measured  in  area  by 
the  polar  planimeter,  and  tabulated  in  Table  I.  The  nucleus- 
plasma  coefficient  for  the  metabiotic  fibers  of  the  normal  con- 
trol dogs  varies  from  10.24  to  11.05,  with  an  average  of  10.65 
for  the  eight  animals,  and  the  greatest  variation  is  7.6  per  cent. 
The  nucleus-plasma  coefficient  for  the  metabiotic  fibers  of  the 
five  normal  rats  varies  from  10.90  to  11.62,  with  an  average  of 
11.45,  and  the  greatest  variation  is  7.1  per  cent.  This  is  a 
remarkable  uniformity  when  it  is  taken  into  consideration  that 
it  holds  for  such  a  wide  range  of  absolute  size. 

While  these  criteria  hold  with  the  constancy  of  a  law,  the 
absolute  size  of  the  metabiotic  fiber  varies  over  a  great  range. 
In  the  case  of  the  normal  control  dogs,  the  average  size  of  the 
metabiotic  fibers  is  216.89  square  micra,  but  the  range  of  size 
is  from  174.49  to  304.01  square  micra  or  a  difference  of  74 
per  cent.  In  the  case  of  the  normal  rats,  the  average  size  is 
166.95  square  micra  but  averages  from  113.35  to  257.30  square 
micra  or  a  difference  of  127  per  cent.  There  is,  consequently, 
a  quantitative  difference  between  one  metabiotic  heart  fiber 
and  another,  between  a  group  of  such  fibers  and  another  group, 
and  between  the  metabiotic  fibers  of  one  animal  and  another 
of  the  same  species. 

The  functional  hypertrophy,  an  anabiotic  adaptation. 

Data  of  experimental  production.  —  Five  dogs  of  the  same  litter  were 
subjected  to  various  degrees  of  activity.  Three  of  the  animals,  of  which 
only  two  will  be  used  in  this  discussion,  were  subjected  to  various  degrees 
of  exercise  in  a  treadmill  and  to  free  outdoor  life.  Two  of  the  five  were 
used  as  controls.  Their  relative  degrees  of  activity  will  be  indicated  in 
later  discussion.  A  more  detailed  account  of  this  series  can  be  found  in  a 
previously  published  paper  on  "The  experimental  production  of  hy- 
pertrophy in  the  nerve  cell"  (Collier,  '22)  which  was  based  upon  the 
nerve  cells  from  these  same  animals. 

Eight  other  young  adult  dogs  were  taken  from  ordinary  life  to  establish 
a  normal  (Table  I) .  The  experimental  animals  should  be  checked  against 
a  normal  average  that  would  include  animals  both  from  active  life  and 
from  a  less  active  one.  With  this  idea  in  mind,  two  of  these  animals, 
Normals  29  and  46,  were  adult  country-bred  dogs  and  two  animals, 
Normals  28  and  30,  were  town-bred  dogs.  The  supposition  was  that 
the  farm-bred  animals  were  more  active  than  the  town-bred  animals, 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE 


217 


TABLE  I.  NUCLEO-CYTOPLASMIC  RELATIONS  OF  METABIOTIC  FIBERS 
OF  DOG  AND  RAT  HEARTS 


Animal 

Cross  sectional 

Nucleus-plasma 
coefficient 

Area  of  fiber 

Area  of  nucleus 

DOGS 
Normal  Control  Series 


Normal  28          

208  7s 

18  17 

IO  24. 

Normal  20 

•3QA    OI 

Of  QT 

IO  7O 

Normal  30  

IQ1.42 

16  41 

II  O1 

Normal  32      

185  80 

15  86 

IO  71 

Normal  33 

187  84. 

15  66 

IO  OO 

Normal  34  

187.  01 

16  41 

IO  3Q 

Normal  35  

174  4Q 

I  1  OO 

10  63 

Normal  46 

291  80 

or  ,18 

10  46 

Average  

216  89 

18  63 

10  65 

Experimental  Control  Series 


Muscular  Exercise  45    

i4i-54 
171.94 

iS-5i 
15.98 

9.12 
0.76 

Muscular  Exercise  41    

Experimental  Hypertrophy  Series 

Muscular  Exercise  44   

200.45 
252.22 

17.99 
21.84 

10.14 
10.50 

Muscular  Exercise  42    

RATS 


Rat  13  

20.30 

21.  18 

II.  14 

Rat  15     .             . 

150.21 

ii  62 

II  62 

Rat  1  8 

I  17  34. 

ii  84 

12  28 

Rat  19  

113.31 

Q.13 

IO.OO 

Rat  20  

124.43 

IO  08 

11.24 

Average 

160  52 

12  85 

II  4-4. 

2l8  COLLIER 

especially  since  one  of  the  latter  was  known  to  have  been  a  pet  house-dog. 
The  other  four  dogs  were  chosen  at  random  without  any  knowledge  of 
their  previous  degree  of  exercise. 

The  morphology  of  the  hypertrophied  fiber  does  not  differ 
in  the  least  detail  from  that  of  the  non-hyper trophied.  And, 
although  the  range  of  size  of  these  fibers  varies  widely,  the 
index  of  the  nucleus-plasma  relationship  remains  constant  in 
large  as  well  as  small  fibers  (Table  I).  The  absolute  size  of 
the  metabiotic  fiber  will  be  used  as  the  index  of  the  degree  of 
anabiosis  and  the  magnitude  of  the  hypertrophy. 

The  correlation  of  this  quantitative  difference  in  size  with 
the  degree  of  excitatory  stimulation  manifested  by  function 
is  suggested  by  a  comparison  of  the  town  and  country  control 
dogs.  The  average  size  of  the  metabiotic  fibers  of  the  town- 
bred  animals  (Normals  28  and  30)  is  202.08  square  micra  and 
of  the  corresponding  fibers  of  the  country-bred  animals  (Nor- 
mals 29  and  46),  297.90  square  micra.  The  difference  between 
these  averages  is  forty-seven  per  cent  in  favor  of  the  relatively 
more  active  country  dogs.  The  hearts  of  these  two  dogs,  whose 
fibers  were  the  largest  of  all  measured,  were  diagnosed  as 
hypertrophied  from  their  gross  size  and  the  thickness  of  the 
ventricles  as  well  as  microscopically.  This  indication  of  a 
correlation  of  size  with  the  degree  of  function  is  made  conclu- 
sive by  the  proportionate  increase  in  size  of  the  fibers  with 
experimental  increase  in  the  degree  of  function  in  the  muscular 
exercise  series. 

The  experimental  control  animals  Muscular  Exercise  41  and 
45  which  were  confined  throughout  life  for  two  and  a  half  and 
three  and  a  half  years,  respectively,  had  comparatively  very 
small  fibers.  Muscular  Exercise  41  which  was  killed  at  the 
beginning  of  the  experiments  had  metabiotic  fibers  which 
average  171.94  square  micra  in  cross  sectional  area,  which  is 
twenty  per  cent  less  than  the  average  of  the  normal  control 
animals.  Muscular  Exercise  45  which  was  killed  at  the  end 
of  the  experiments  had  metabiotic  fibers  which  average  141.54 
square  micra  or  thirty-five  per  cent  smaller  than  the  average 
of  the  normal  control  animals  and  seventeen  per  cent  smaller 
than  those  of  the  experimental  control  killed  at  the  beginning 


ADAPTIVE  CHANGES  OF  HEART  MUSCLE 


2IQ 


of  the  experiments  (Muscular  Exercise  41).  It  is  evident  that 
the  animals  just  discussed  were  in  a  state  of  relative  katabiosis 
from  underf unction,  and  in  the  case  of  Muscular  Excerise  45 
one  may  deduce  a  disuse  atrophy  after  some  degree  of  size  has 
been  attained,  because  the  animal  was  confined  for  the  last 
year  in  a  cage  with  a  floor  space  one-third  as  large  as  for  the 
former  two  years  and  half.  These  animals  are  introduced 
here  for  the  sake  of  comparison  with  the  more  exercised 
animals  to  emphasize  the  degree  of  hypertrophy  and  to  indi- 
cate the  great  range  in  size  correlated  with  different  degrees  of 
function. 

Muscular  Exercise  44  was  allowed  a  year  of  outdoor  life 
plus  a  small  amount  of  work  in  the  treadmill.  The  metabiotic 
fibers  average  200.45  square  micra  or  eight  per  cent  smaller 

TABLE  II.  LENGTH  OF  SARCOMERES  IN  MICRA 


Normal  29 

Muscular  exercise  42 

Normal  30 

Muscular  exercise  45 

2.73 

2.84 

2.47 

2.47 

2.52 
2.31 
2.14 

2.52 
2.42 
2.18 

2.24 
2.IO 
I.Q2 

2.21 
2.18 
1.84 

than  the  average  of  the  normal  control  animals  but  twenty-one 
per  cent  larger  than  those  of  the  experimental  controls. 

The  most  exercised  animal,  Muscular  Exercise  42,  was  given 
regular  exercise  in  the  treadmill  plus  normal  outdoor  life  for  a 
year.  Its  metabiotic  fibers  average  252.22  square  micra  in 
cross  section  or  twenty  per  cent  larger  than  the  average  of 
those  of  the  normal  control  animals  and  sixty-one  per  cent 
larger  than  the  average  of  those  of  the  two  experimental  con- 
trols. Actually,  the  exercise  brought  the  size  of  this  dog's 
fibers  from  one  corresponding,  presumptively,  to  the  smallest 
size  of  the  experimental  controls  to  the  third  largest  of  all 
dog  hearts  measured,  next  to  the  known  hypertrophy  of  the 
country  dogs,  Normals  29  and  46.  These  had  had  whole  lives 
of  exercise.  Even  Muscular  Exercise  44  was  brought  to  fifth 
place. 


220  COLLIER 

That  there  is  an  increase  in  the  size  of  the  fiber  is  confirmed 
by  the  fact  that  the  increase  in  the  cross  sectional  area  of  the 
fiber  is  accompanied  by  an  increase  in  the  length  of  the  indi- 
vidual sarcomere.  The  data  in  Table  II  are  the  average 
measurements  in  micra  of  the  sarcomeres  in  each  of  the  four 
animals  so  studied.  The  four  figures  given  under  each  animal 
represent  four  arbitrarily  chosen  degrees  of  contraction.  The 
largest  figure  represents  the  length  of  the  sarcomere  in  the 
relaxed  condition.  The  smallest  figure  represents  the  length 
of  the  sarcomere  in  the  most  contracted  condition.  The  two 
intermediate  figures  represent  two  intermediate  stages.  Each 
figure  represents  the  average  derived  from  the  measurement 
of  fifteen  groups  of  sarcomeres,  each  group  consisting  of  ten 
contiguous  sarcomeres.  Each  figure  represents,  then,  the 
average  length  of  the  sarcomere  derived  from  the  measurement 
of  one  hundred  and  fifty  sarcomeres. 

The  animals  with  minimal  exercise,  Normal  30  and  Mus- 
cular Exercise  45,  had  sarcomeres  which  were  fourteen  per  cent 
shorter  than  those  of  the  more  exercised  animals,  Normal  29 
and  Muscular  Exercise  42.  These  data  demonstrate  that  the 
degree  of  anabiosis  can  be  estimated  either  by  the  measure- 
ment of  the  cross  sectional  area  of  the  metabiotic  fiber  or  by 
the  measurement  of  the  length  of  the  sarcomeres  so  long  as 
contracted  fibers  are  compared  with  contracted  fibers  and 
relaxed  fibers  with  relaxed  fibers.  One  set  of  data  can  also  be 
checked  against  the  other,  which  is  of  value  since  the  fiber  in 
cardiac  dilatation  is  increased  in  length  but  the  cross  sectional 
area  is  decreased,  as  will  be  discussed  more  in  detail  later, 
whereas  in  hypertrophy  both  dimensions  are  increased.  The 
figures  of  this  table  also  demonstrate  that  it  is  possible  to 
check  the  diagnosis  of  the  state  and  stage  of  contraction  or 
relaxation  in  a  given  animal  by  actual  measurements  of  the 
length  of  the  sarcomeres.  It  can  be  confessed  that  the  reason 
for  the  measurement  of  the  length  of  the  sarcomeres  was  an 
attempt  to  check  the  diagnosis  of  the  degree  of  contraction  and 
the  observation  that  such  a  mathematical  diagnosis  of  the 
degree  of  contraction  was  possible  was  overshadowed  by  the 
accidental  and  much  more  important  observation,  for  example, 


ADAPTIVE  CHANGES  OF  HEART  MUSCLE  221 

in  differentiating  hypertrophy  and  dilatation,  that  the  meas- 
urements of  the  length  of  the  sarcomere  have  a  definite  relation 
to  the  data  of  the  cross  sectional  area  measurements. 

The  nature  and  significance  of  the  functional  hypertrophy. 
—  Most  discussions  of  hypertrophy  are  confused  by  the  appli- 
cation of  the  same  term  to  two  or  more  different  processes;  to 
an  increase  in  the  size  of  the  cell,  to  an  increase  in  the  size  of 
the  organ,  and  to  an  increase  in  the  number  of  cells.  The 
second  confusion  arising  in  the  literature  is  the  failure  of  the 
workers  to  differentiate  between  the  two  states  of  cell  enlarge- 
ment, that  is,  between  hypertrophy  proper  and  cloudy  swelling. 
Virchow  as  early  as  1858  defined  hypertrophy  as  a  true  growth 
and  differentiated  it  from  the  cell  enlargement  of  degenerative 
changes  by  certain  definite  cytological  differences  ('58,  93). 

The  present  conceptions  of  the  nature  and  significance  of 
hypertrophy  appear  to  be  divided  between  the  pathological 
and  the  physiological. 

The  pathological  conception  of  hypertrophy. 

The  identity  of  hypertrophy  and  degeneration.  —  Minot  ('08,  71) 
says  that  hypertrophy  is  in  itself  a  degenerative  change  and  concludes  the 
chapter  with  the  following  sentences.  "Another  form  of  degeneration 
which  occurs  in  many  cases  is  of  great  interest  because  it  seems  as  if  the 
cells  were  making  a  last  great  effort ;  and  their  performance  is  one  of  en- 
largement. This  form  of  degeneration  is  termed  hypertrophy."  Minot 
is  describing  a  state  of  katabiosis  leading  to  exhaustion,  namely,  a  cloudy 
swelling.  It  is  not  a  true  hypertrophy,  that  is,  overgrowth. 

A  compensatory  sequel  to  some  pathological  lesion.  —  The  prevalent 
opinion  seems  to  be,  however,  that  hypertrophy  is  the  result  of  degenera- 
tive changes.  That  is,  since  it  occurs  most  commonly  accompanying  or 
following  some  pathological  lesion,  it  appears  to  be  the  invariable  result 
of  a  pathological  "cause"  and,  therefore,  to  be  of  an  abnormal  character 
itself.  Some  of  the  commoner  text  book  causes  may  be  outlined  as 
follows: 

Compensation  to  inflammation. 

General  and  coronary  arterio-sclerosis  of  inflammatory  (or  non- 
inflammatory) origin. 
Chronic  fibrous  myocarditis. 

Acute  exudative  or  chronic  fibroid  pneumonitis  or  emphysema. 
Chronic  interstitial  nephritis. 
Valvular  deficiencies. 
Excess  fluid  content  of  the  blood  (Munich  beer  heart). 


222  COLLIER 

Disturbed  nervous  control  (Thyroid,  suprarenal,   vasomotor  dis- 
orders). 

Chemical  irritation  (Toxins  and  drugs). 
Muscular  work. 

Physiological  conception  of  hypertrophy.  —  The  pathological  con- 
ception of  hypertrophy  is  so  generally  accepted  that  the  one  instance  of 
hypertrophy  which  is  not  preceded  or  accompanied  by  a  pathological 
lesion,  namely,  muscular  overwork,  is  usually  set  aside  as  an  entirely 
different  proposition  and  designated  as  a  physiological  or  even  as  an  idio- 
pathic  hypertrophy.  The  latter  term  is  used  to  express  that  there  is  no 
etiological  pathological  lesion  and  that  hypertrophy  happens,  therefore, 
for  some  mysterious  unexplainable  reason.  Nevertheless,  some  men 
have  had  the  physiological  conception  of  hypertrophy  although  initiated 
by  a  pathological  lesion. 

Rosenbach  ('78,  9)  attributes  the  mechanism  of  hypertrophy  to  a  pro- 
portionate overwork  of  the  contractile  substance  of  the  heart  to  com- 
pensate for  the  increased  resistance  to  the  blood  flow. 

Goldenberg  ('86,  88)  and  a  group  of  men  working  with  him  found  by 
actual  measurement  of  the  fibers  that  heart  hypertrophy  is  due  to  an 
increase  in  the  size  of  the  muscle  fiber  and  not  to  an  increase  in  the  num- 
ber of  fibers.  Goldenberg  reviews  the  work  of  former  investigators  and 
states  that  J.  Vogel,  Kolliker,  Foerester,  Lebert,  Hyrtl,  and  Rokitansky 
agreed  that  the  state  of  hypertrophy  is  attained  by  a  hyperplasia  of  the 
muscle  fibers;  that  Wilks  and  Rindfleisch  lay  the  increase  in  volume  of 
the  heart  to  an  increase  in  the  number  of  fibers  to  lengthwise  splitting; 
that  Hepp,  Robin,  Wedl,  Bequel,  Friedreich,  Zenker,  and  Lancereaux 
measured  fibers  and  found  that  the  individual  fiber  is  increased  in  size. 
Goldenberg  concludes  for  the  group  who  ascribe  the  hypertrophy  to  an 
increase  in  the  size  of  the  muscle  fiber  that  function  of  the  musculature 
gradually  builds  up  not  only  a  macroscopical  increase  in  heart  muscle 
volume,  but  also  a  microscopical  increase  in  breadth  of  the  heart  muscle 
fiber  through  an  inflow  of  material  into  the  cell. 

Hasenfeld  and  Romberg  ('97, 371)  have  added  the  observation  that  the 
degree  of  hypertrophy  is  directly  proportional  to  the  magnitude  of  the 
valvular  insufficiency  which  initiated  the  hypertrophy.  This  is  in  accord 
with  the  present  work  demonstrating  that  growth  is  quantitatively  pro- 
portional to  the  intensity  of  the  stimulus  so  long  as  the  intensity  is  favor- 
able for  the  production  of  hypertrophy. 

Tangl  ('06,  432)  concludes  that  there  is  an  increase  in  the  diameter  of 
the  fiber  which  agrees  with  the  findings  of  Goldenberg  and  with  the  data 
presented  in  this  work.  He  also  finds  that  there  is  an  increase  in  the 
length  of  the  hypertrophied  fiber  which  I  have  confirmed  by  the  measure- 
ments of  the  individual  sarcomere  with  identical  results.  He  agrees  with 
the  histological  findings  of  Goldenberg  and  Leutelle  that  there  is  no  evi- 
dence of  mitosis  of  the  cell  nor  any  evidence  of  an  amitotic  division  of  the 
nucleus.  He  states  that  the  histological  evidence  of  inflammation  was 
found  in  the  later  stages  of  hypertrophy,  by  which  he  means  the  edema 
and  disintegrative  changes  of  overexcitation,  but  he  concludes  that  there 
is  not  sufficient  proof  of  a  consistent  relationship  between  inflammation 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE  22$ 

and  hypertrophy  and  with  Leutelle  ('88)  is  unable  to  define  two  types  of 
hypertrophy,  namely,  a  hypernutritive  and  a  degenerative.  It  must  be 
remembered  that  he  is  a  contemporary  of  Minot  and  is  denying  the 
assertion  that  hypertrophy  is  a  degeneration  as  Minot  and  others  thought 
and  is  concluding  in  favor  of  a  physiological  significance  for  the  process  of 
hypertrophy. 

At  the  same  time,  Kulbs  ('06,  28)  became  dissatisfied  with  the  explana- 
tion that  cardiac  hypertrophy  is  the  reaction  to  a  pathological  necessity. 
He  used  treadmill  exercise  to  produce  a  hypertrophy  that  would  be  un- 
complicated by  valvular  insufficiencies,  arterio-sclerosis,  kidney  diseases, 
etc.  He  removed  all  pathological  conditions  from  his  experimental 
method  and  produced  his  hypertrophies  by  simply  working  his  dogs  in  a 
treadmill  in  a  manner  similar  to  the  method  which  I  used.  His  results 
were  identical  with  those  obtained  in  the  course  of  the  present  work 
which  are  tabulated  in  Table  I. 

The  mechanism  of  the  organic  relationships  involved  in 
hypertrophy  of  the  heart.  —  Such  data  demonstrate  a  corre- 
lation of  quantitative  differences  in  size  with  quantitative 
degrees  of  body  function.  This  relation  has  been  concisely 
stated  by  Hirsch  (Joo),  "The  mass  of  heart  muscle  is  the  ex- 
pression of  the  degree  of  body  work."  The  most  important 
theories  to  explain  this  correlation  are  the  mechanical  and  the 
nervous.  The  nervous  side  is  fully  accepted  but  not  to  be 
discussed  in  detail  because  it  belongs  to  the  general  nervous 
control  of  the  heart.  A  mechanical  theory  will  be  discussed 
to  show  that  the  principle  underlying  the  production  of  hyper- 
trophy is  identical  in  all  cases,  whether  due  to  increased  re- 
sistance conditioned  by  body  work  or  by  a  pathological  lesion. 

Muscular  exercise  distends  the  heart  through  forces  working 
from  both  the  venous  and  the  arterial  side.  Tension  is  applied 
from  the  venous  side  in  two  ways:  the  increased  respiratory 
movements  accompanying  muscular  exercise  suck  a  greater 
amount  of  blood  into  the  right  auricle  in  a  given  period  of  time 
and  the  increased  muscular  contractions  milk  the  blood  out 
of  the  capillaries  and  veins  into  the  heart,  thus  increasing  the 
venous  pressure  and  the  tension  upon  the  right  side  of  the 
heart  during  diastole  (Howell,  'u,  508-9).  From  later  state- 
ments from  the  same  author,  the  conclusion  can  be  drawn 
that  the  amplitude  of  the  venous  pressure  determines  the  in- 
tensity of  the  stimulus  to  contraction  which  determines  the 
rate  and  the  amplitude  of  the  contraction  (Howell,  '19,  552). 


224  COLLIER 

The  work  of  Tangl  and  Zunst  ('98,  544)  demonstrates  that 
muscular  activity  increases  the  arterial  blood  pressure  from 
117  mm.  to  238  mm.  of  mercury  in  the  case  of  the  dog  doing 
work  quite  comparable  to  the  treadmill  work.  Thus  from  the 
arterial  side  as  on  the  venous  side,  tension  is  placed  upon  the 
heart  during  diastole.  H.  A.  Stewart  ('n)  says,  "Hyperten- 
sion applied  to  the  ventricular  wall  during  diastole  is  a  most 
potent  factor  in  increasing  the  force  of  systolic  contraction." 
This  may  be  accepted  so  long  as  the  degree  of  tension  and  the 
nutritional  state  are  within  certain  limits. 

Likewise,  the  pathological  lesions  act  to  produce  either  a 
general  increased  tension,  as  just  discussed,  or  a  local  one. 

A  local  increased  tension  conditioned  by  a  pulmonary  steno- 
sis, by  an  increased  resistance  to  the  blood  flow  through  the 
lungs,  by  arterio-sclerosis,  by  chronic  nephritis,  by  excess  fluid, 
or  by  an  aortic  stenosis  would  only  distend  a  local  portion  of 
the  heart  and  stimulate  it  to  overwork  unless  the  stimulus  was 
of  such  a  degree  that  it  in  turn  affected  other  portions. 

Thus,  regardless  of  whether  the  hypertrophy  produced  is 
"caused"  by  a  valvular  deficiency,  a  pneumonitis,  a  myocar- 
ditis, an  interstitial  nephritis,  an  excess  fluid  content  of  the 
blood,  an  arterio-sclerosis,  or,  as  is  demonstrated  in  this  paper, 
body  overwork,  the  common  effect  is  that  of  a  relatively 
greater  tension  upon  the  muscular  walls  of  the  heart  as  a  whole 
or  locally,  conditioned  upon  a  relative  or  absolute  increase  of 
resistance.  Thus,  Stewart's  hypertension  theory  accounts  for 
a  great  variety  of  localized  cardiac  hypertrophies  and  Howell's 
venous  hypertension  theory  furnishes  a  basis  for  the  regulated 
hypertrophy  of  the  whole  organ  in  certain  conditions.  The 
objection  to  Stewart's  theory  as  an  all  sufficient  theory  to 
explain  hypertrophies  is  that  he  deals  with  mechanical  to  the 
exclusion  of  nervous  and  chemical  stimulation. 

The  rest  of  the  text  book  causes,  exophthalmic  goiter,  vas- 
omotor  and  suprarenal  disorders,  chemical  irritants,  either 
toxins  or  drugs,  and  the  reflex-nervous  excitation  of  the  heart 
in  overwork  can  affect  the  heart  only  quantitatively  through 
the  normal  nervous  control  or  through  the  conductile  mechan- 
ism of  the  heart  or  through  both  by  increasing  the  rate  and 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE  225 

intensity  and  conductivity  of  stimulation.  Consequently,  re- 
gardless of  the  kind  of  stimuli,  mechanical,  nervous,  or  chemi- 
cal, all  the  " causes"  have  a  common  effector,  overstimulation, 
and  the  conclusions  drawn  for  one  stimulus  are  applicable  to 
all.  The  experimental  data  of  the  next  section  will  entirely 
exclude  any  specificity  of  stimuli. 

The  term  "cause"  has  been  used  in  this  discussion  because 
it  is  the  absolutely  necessary  term  to  convey  the  interpretation 
that  the  text  book  writers  place  upon  the  etiological  signifi- 
cance of  the  relationship  of  these  pathological  lesions  to  the 
cardiac  hypertrophy.  Speaking  for  the  heart,  there  is  no 
foundation  for  any  cause  and  effect  relationship  because  any 
of  the  above  named  pathological  or  physiological  factors  may 
condition  either  hypertrophy  or  organic  exhaustion  and  atrophy 
or  depression  and  atrophy,  which  will  be  discussed  at  length 
in  the  following  section,  depending  upon  the  rate  and  intensity 
of  the  stimuli  and  the  nutritional  state  of  the  fiber.  Thus, 
hypertrophy  is  not  caused  but  may  be  conditioned  if  the  rate 
and  intensity  of  the  stimuli  and  the  state  of  nutrition  are 
favorable.  For  the  same  reason  the  term  "compensatory" 
hypertrophy  is  objectionable.  There  is  no  inherent  purpose 
to  compensate  invested  in  the  properties  of  the  cell  because  if 
the  stimuli  are  of  insufficient  rate  and  intensity,  the  hyper- 
trophy does  not  compensate;  if  the  stimuli  are  of  too  great 
rate  and  intensity,  the  hypertrophy  does  not  compensate  and, 
in  fact,  may  go  to  organic  exhaustion  and  atrophy;  but  if  the 
rate  and  intensity  lies  between  these  two  extremes  and  if  the 
nutritional  state  is  sufficient,  hypertrophy  is  conditioned  and 
affords  physiological  adaptation  for  the  preexisting  deficiency. 
The  only  conception  that  accounts  for  the  initiation  of  hy- 
pertrophy as  well  as  for  the  failure  of  its  initiation  is  that  of 
conditionality.  It  is  upon  this  idea  that  the  physiological 
interpretation  of  the  etiology  of  hypertrophy  is  based.  The 
physiological  conception  of  the  incidence  of  hypertrophy  fol- 
lowing a  pathological  process  is  that  it  is  the  adaptation  to  the 
altered  relation  of  the  normal  properties  of  the  cell  influenced 
by  the  pathological  process. 


226  COLLIER 

The  cellular  mechanics  of  hypertrophy.  —  Hypertrophy,  or 
growth  after  cell  maturity,  is  the  physiological-anatomical 
manifestation  of  an  increased  metabolism  initiated  by  a  quan- 
titatively greater  degree  of  stimulation. 

Its  cellular  mechanics  are  based  upon  the  fundamental 
property  of  irritability  coordinated  with  the  equally  funda- 
mental property  of  metabolism.  Thus,  Thoma  says  that,  as 
R.  Virchow  showed,  growth,  irritability,  and  metabolism  are 
the  three  interdependent  vital  phenomena  of  the  cell.  If  these 
three  fundamental  properties  are  interdependent,  it  can  be 
deduced  that  there  is  no  specificity  of  stimuli.  This  will  be 
experimentally  demonstrated  for  the  heart  in  the  next  section. 
Verworn  defines  the  irritability  of  living  substance  as,  "Its 
ability  of  reaction  to  changes  in  its  environment  by  changes  in 
the  equilibrium  of  its  matter  and  energy ";  and,  "changes  in 
its  environment,"  he  calls  stimuli  ('96,  353).  Consequently, 
if  the  presence  of  hypertrophy  depends  upon  stimulation,  the 
conclusions  derived  for  any  one  stimulus  are  applicable  to  all 
kinds  of  stimuli. 

The  data  presented  in  Tables  I  and  II  and  the  text  of  the 
foregoing  discussion  demonstrate  that  the  size  of  the  fiber  is 
directly  proportional  to  the  degree  of  cardiac  stimulation. 
The  next  step  is  to  correlate  stimulation  with  metabolism. 

These  quantitative  changes  in  the  size  of  the  cell  and,  it 
will  be  shown,  their  corresponding  quantitative  intensities 
of  specific  energy  production  are  the  manifestations  of  "the 
changes  in  the  equilibrium  of  its  matter  and  energy."  These 
changes  are  functions  of  cell  metabolism  involving  upon  the 
assimilative  side  the  formation  of  the  more  complex  substances 
from  the  simpler  substances  gained  from  the  blood  with  the 
storing  of  potential  energy;  and,  upon  the  dissimilative  side 
the  reduction  of  the  more  complex  compounds  of  the  cell  into 
simpler  compounds  with  the  coincident  liberation  of  the  stored 
potential  energy  in  the  form  of  kinetic  energy  manifested  for 
the  most  part  in  the  performance  of  function.  It  follows  that 
growth  is  the  manifestation  of  the  assimilative  side  of  metabo- 
lism and  that  functional  energy  production  is  the  manifestation 
of  the  dissimilative  side  of  metabolism.  In  the  metabiotic 


ADAPTIVE  CHANGES  OF  HEART  MUSCLE        227 

fiber,  the  dissimilative  processes  are  exactly  balanced  by  the 
assimilative  processes,  as  demonstrated  by  the  constancy  of 
the  nucleus-plasma  coefficient.  Since  the  intensity  of  the  liber- 
ation of  energy  for  function,  which  is  the  manifestation  of  the 
dissimilative  side  of  metabolism,  is  increased  in  the  hyper- 
trophied  fiber,  the  assimilative  side  of  metabolism,  growth 
(hypertrophy),  must  be  correspondingly  increased.  The 
metabolic  nucleo-cytoplasmic  equilibrium  of  the  non-hyper- 
trophied  cell  is  retained  in  the  hypertrophied  cell  which  de- 
mands that  if  one  phase  of  metabolism  is  increased  that  both 
phases,  assimilatory  and  dissimilatory,  must  be  increased. 
This  seems  to  allow  only  of  the  conclusion  that  an  increased 
size  of  the  cell  and  an  increased  production  of  functional  energy 
are  accomplished  by  an  increase  in  the  rate  of  the  non-hyper- 
trophied  cell  metabolism.  Consequently,  the  intensity  of  the 
specific  energy  production,  work,  and  the  size  of  the  cell  are 
the  manifestations  of  a  quantitatively  greater  rate  of  metabo- 
lism. 

Verworn  states  this  relationship  of  size  and  function  not 
upon  the  basis  of  metabolism  as  it  has  been  developed  here, 
but  upon  the  obvious  anatomical  relationship.  "Die  Intensi- 
tat  der  spezifischen  Energieproduktion  einer  Ganglienzelle  eine 
Funktion  der  Masse  ihrer  entladungsfahigen  Substanz  ist," 
and  states  that  this  law  laid  down  for  the  nerve  cell  also  ap- 
plies to  the  muscle  cell,  "Eine  grosserer  Masse  eines  explosiben 
Stoffes  liefert  bei  der  Explosion  naturlich  eine  grossere  Menge 
Energie  als  eine  kleinere  Masse;  ein  grosserer  Muskel  produ- 
ziert  bei  gleichstarker  Reizung  mehr  Energie  als  ein  kleinerer" 
('07,  131).  Thus  the  size  of  the  metabiotic  fiber  determines  its 
intensity  of  specific  energy  production. 

Therefore,  in  conclusion,  both  the  intensity  of  the  specific 
energy  production  and  the  size  of  the  fiber  are  the  manifesta- 
tions of  a  quantitative  rate  of  metabolism.  The  relationship  of 
stimulation  to  irritability,  namely,  "changes  in  the  equilibrium 
of  cell  matter  and  energy,"  of  which  cell  metabolism,  cell 
function,  and  cell  size  are  manifestations,  is  quantitative.  A 
greater  degree  of  stimulation  induces  a  greater  degree  of  irri- 
tability which  is  manifested  by  a  greater  rate  of  metabolism; 


228  COLLIER 

this,  in  turn,  conditions  a  greater  intensity  of  function  and  a 
larger  cell  so  long  as  the  rate  and  intensity  of  the  stimuli  are 
adjusted  to  the  nutritional  state  of  the  fiber. 

The  view  of  adaptation  as  the  resultant  of  the  increased  de- 
gree of  stimulation  is  applicable  to  all  forms  of  hypertrophy, 
and,  conversely,  all  hypertrophies  are  referable  to  the  funda- 
mental principle,  already  stated,  that  the  physiological- 
anatomical  complex  of  function,  metabolism,  and  growth  is 
the  objective  manifestation  of  any  excitatory  stimulation. 
The  same  view  is  equally  applicable  to  the  failure  of  hyper- 
trophy under  its  usual  conditions,  —  the  stimuli  may  be  defi- 
cient or  excessive  in  duration  and  rate,  so  that  disuse  atrophy 
or  exhaustion  atrophy  are  equally  provided  for.  So  far  as 
concerns  the  hypertrophy  proper,  namely,  the  increase  in  size 
of  the  cell  unit,  the  distinction  between  simple  and  pathologi- 
cal hypertrophies  is  nonexistent.  All  hypertrophies  are  physi- 
ological in  origin  and  nature,  although  they  may  reach  a 
pathological  state  in  their  degree,  and,  in  fact,  they  usually  do. 

Katabiotic  adaptive  processes.  —  The  discussion  has  been 
heretofore  confined  to  a  regulated  overexercise  in  which  the 
factors  of  anabolism  and  katabolism  are  in  a  state  of  equi- 
librium. Katabiosis  is  the  process  that  results  if  the  rate  and 
intensity  of  stimulation  and  the  nutritional  state  are  not  favor- 
able for  one  or  all  fibers  at  a  particular  time.  Thus,  this  section 
of  the  paper  is  concerned  with  an  upset  of  the  condition  of 
metabolic  nucleo-cytoplasmic  equilibrium  by  overexcitation 
or  depression.  The  study  of  the  cytomorphosis  correlated 
with  degrees  of  stimulation  has  been  experimentally  under- 
taken by  the  use  of  trophic,  thermic,  nervous,  and  various 
chemical  stimuli  in  various  degrees  and  dosages  and  over 
various  periods  of  time. 

However,  such  changes  of  stimulation  are  present  in  a  less 
degree  in  all  normal  animals.  Moreover,  in  all  of  the  dogs  dis- 
cussed in  the  foregoing  section,  there  were  katabiotic  fibers  as 
well  as  metabiotic  fibers,  that  is,  the  rate  and  intensity  of  stim- 
ulation were  not  altogether  suitably  adjusted  to  the  metabo- 
lism. They  were  tacitly  ignored  at  that  time  to  avoid  confusion. 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE 


229 


It  was  because  of  the  presence  of  these  katabiotic  fibers  that 
the  diagnosis  of  the  metabiotic  state  was  indispensable  for 
comparison.  Metabiosis  is  a  state.  Katabiosis  is  a  process 
which  has  many  degrees,  the  magnitude  of  which  may  be 

TABLE  III.  DATA  OF  DRUG  ADMINISTRATION 


Animal 

Weight  in 
grams 

Dose  per  day 

Duration  ot 
experiment 

Total  dosage 

Digitalis  Series 


IO 

130 

.006 

10  days 

.06 

II 

180 

.006 

42  days 

.252 

23 

1  60 

.024 

17  days 

.408 

r.oo6 

30  days  ) 

27 

150 

•j  .024 

21  days  f 

•543 

1.0015 

14  days] 

28 

200 

.0015 

30  days 

•045 

30 

220 

.0015 

21  days 

•0315 

Cocaine  Series 


4 

.20* 

3    days 

i.  20 

5 

.... 

.20* 

2    days 

.80 

3 

.20* 

i£  days 

.60 

Pilocarpine  Series 


2 

I 

1  2O 
125 

•3t 
•3t 

89  days 
100  days 

26.7 
30.0 

*  Twice  daily. 


t  Rest  every  third  day. 


roughly  determined  by  the  change  of  the  index  of  the  nucleo- 
cytoplasmic  relationship  above  or  below  that  of  the  metabiotic 
fiber. 

Experimental  data.  —  Most  of  the  data  presented  in  conjunction  with 
this  portion  of  the  paper  are  derived  from  rat  hearts,  the  remainder  from 
dogs.  The  fact  was  appreciated  that  the  use  of  two  species  of  animals 
would  furnish  a  more  general  basis  for  deductions.  Of  the  thirty  rats 
used,  five  were  normals.  The  dosage  and  the  duration  of  the  drug  ad- 
ministration are  given  in  Table  III. 


230  COLLIER 

Rats  16,  17,  24,  25,  and  30  compose  a  series  of  experiments  to  demon- 
strate the  correlation  of  morphological  changes  with  the  partial  or  com- 
plete deprivation  of  the  rat  of  its  oxygen  supply.  The  method  used  to 
eliminate  the  greater  part  of  the  oxygen  was  to  substitute  hydrogen  for 
air  by  passing  a  stream  of  hydrogen  through  an  enclosed  chamber. 

Rat  1 6  was  subjected  to  three  consecutive  hours  in  the  hydrogen 
chamber. 

^  Rat  17  was  subjected  to  two  shifts  of  ten  hours  each  during  which 
time  pure  air  was  admitted  for  ten  minutes  in  every  forty.  There  was  a 
period  of  fourteen  hours  rest  outside  of  the  chamber  between  the  two 
shifts.  The  animal  was  killed  by  asphyxiation  in  the  chamber. 
;  |  Rats  24  and  25  were  subjected  to  the  same  experiment  in  the  same 
way  as  Rat  17  except  that  the  period  was  four  times  as  long. 

Rat  30  was  subjected  to  the  same  method  in  the  same  way  for  a  period 
of  seventy  days  with  a  period  of  rest  of  seven  days  from  the  eighth  to  the 
fifteenth  day. 

Rat  26  was  subjected  to  a  temperature  of  40°  C.  in  a  well-ventilated 
oven  for  two  and  one-half  hours  per  day  for  three  weeks.  The  object  was 
to  ascertain  the  effect  of  heat  on  so  highly  specialized  an  organ  as  the 
heart,  bearing  in  mind  the  general  law  that  heat  within  certain  limits  of 
degree  increases  the  rate  and  intensity  of  the  fundamental  processes  of 
the  cell. 

Rat  6  was  operated  upon  and  one  kidney  removed.  It  was  killed  two 
days  after  the  operation  from  which  the  animal  had  not  fully  recovered. 

Rat  9  was  given  a  very  small  dose  of  caffein  per  day  for  ten  days  in 
order  to  produce  the  intercalated  discs  which  are  associated,  in  the  litera- 
ture, with  caffein  administration. 

Four  dogs  were  used  to  demonstrate  that  the  changes  described  in 
detail  for  the  rat  are  also  common  to  the  dog  in  every  respect.  However, 
the  dog's  heart  is  more  resistant  to  these  changes  than  the  heart  of  the 
rat.  It  is  possible  that  this  fact  is  due  to  the  greater  rate  of  contraction 
in  the  rat  which  would  permit  less  time  for  recuperation.  Its  adaptive 
powers  would  thus  be  more  limited. 

Muscular  Exercise  43,  which  was  described  in  the  data  for  the  func- 
tional hypertrophy,  was  in  a  toxic  state  from  infection. 

Dog  36  was  given  strychnine  continuously  until  the  lethal  dose  pro- 
duced death  six  hours  after  the  beginning  of  the  experiment. 

Dog  37  was  a  rabid  animal  which  had  passed  through  the  excitation 
stage  and  was  in  a  state  of  coma  when  it  died. 

Normal  31  demonstrated  a  cardiac  functional  disorder  on  the  cardia- 
gram  which  was  diagnosed  by  the  physiologist  as  an  abnormal  vagus 
stimulation. 

Mechanics  of  katabiosis  from  overexcitation.  —  The  mor- 
phological evidences  of  katabiosis  from  overexcitation  which 
have  been  explained  in  detail  in  the  previous  section  are:  the 
progressive  edema,  the  loss  of  chroma  tin  from  the  nucleus,  the 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE  231 

disintegration  of  the  cross  stria tions  to  the  degree  of  meta- 
morphic  change,  the  breaking  up  of  the  sarcomeres,  and  the 
vacuolization  of  the  sarcoplasm.  The  progressive  edema  is 
the  manifestation  of  an  increased  osmotic  pressure  which 
Cook  ('98),  Loeb  ('94),  and  Stewart  ('n)  have  demonstrated 
in  the  immediate  reaction  to  overstimulation.  The  majority 
of  the  writers  favor  the  opinion  that  muscular  contraction  and 
relaxation  are  based  fundamentally  upon  the  physico-chemical 
reactions  of  the  cross  st nations.  An  increased  rate  and  in- 
tensity of  excitatory  stimulation  is  quantitatively  associated 
with  a  conversion  of  the  cell  structure  into  energy  as  is  made 
evident  by  the  loss  of  chromatic  material  from  the  cross  stria- 
tions  and  from  the  nucleus  and  the  disintegration  of  the  cell 
structure.  The  alterations  demonstrate  that  the  destructive 
process  of  the  fiber  exceeds  the  constructive  process.  Thus, 
in  overexcitation,  the  duration  and  rate  of  the  stimuli  are  of 
such  a  degree  that  the  metabolism  of  that  moment  is  unbal- 
anced in  favor  of  the  oxidative  destructive  changes,  and,  if  the 
duration  and  rate  of  the  stimuli  are  not  altered  in  degree  to 
allow  for  recuperation,  the  destructive  phase  of  metabolism 
becomes  progressively  predominant  and  the  metabolism  re- 
cedes progressively  farther  from  the  state  of  metabiosis. 

The  metamorphic  change  of  the  extranuclear  chromatin  in 
the  cross  striations,  which  has  been  discussed  as  a  characteristic 
change  in  the  latter  stages  of  overexcitation,  is  clearly  the  end 
phase  of  an  identical  regressive  process.  The  regressive  proc- 
ess is  made  evident  by  a  gradual  decrease  in  the  affinity  of  the 
cross  striations  for  hematoxylin.  From  the  point  of  view  of 
staining  reactions,  it  seems  that  the  extranuclear  chromatic 
material  as  well  as  the  nuclear  material  is  used  up  in  overfunc- 
tion,  for  the  regressive  intensity  of  staining  approaching  the 
metamorphic  change  of  the  cross  striations  occurs  concurrently 
with  the  progressive  diminution  of  nuclear  substance. 

Mechanics  of  katabiosis  from  depression.  —  Measurements 
have  shown  that  in  depression  the  cross  sectional  area  is  de- 
creased but  the  length  of  the  sarcomere  is  increased.  This  is 
still  in  accordance  with  the  statement  that  the  volume  of  the 


232  COLLIER 

sarcomere  is  decreased,  because  the  increase  in  length  is  dis- 
proportionate to  the  decrease  in  area.  However,  the  shrinkage 
in  volume  does  not  seem  to  account  for  all  of  the  increase  in 
substance  per  unit  volume.  At  least,  the  simple  explanation 
of  shrinkage  will  not  account  for  the  denser  staining  of  the 
nucleus,  because  in  the  early  stages  of  depression  the  volume 
and  amount  of  chromatic  substance  is  both  relatively  and 
absolutely  increased. 

From  the  analogy  with  other  depressions,  part  of  the  in- 
creased eosinophilia  of  the  cytoplasm  may  be  due  to  an  in- 
creased density  of  substance  following  an  assimilation  of  raw 
foodstuffs  which  are  not  synthesized  into  cell  structure.  Popoff 
('09)  demonstrated  the  inability  to  synthesize  raw  food  into 
cell  structure  in  the  case  of  depressed  paramaecia.  A  year 
earlier  ('08),  he  found  that  yolk  material,  fat,  and  glycogen 
are  deposited  in  the  cytoplasm  of  depressed  metazoan  sex  cells, 
and,  still  earlier,  that  eosinophilius  granules  are  deposited  in 
depressed  somatic  cells  ('07).  Reichenow  ('08)  found  unsyn- 
thesized  food  in  the  intestinal  epithelium  of  the  depressed 
frog.  Dolley  ('13)  found  an  opacity  associated  with  eosino- 
philia as  well  as  discrete  eosinophilic  globules  in  the  depressed 
nerve  cell,  both  of  which  he  interpreted  as  unsynthesized  al- 
buminous material.  Further,  as  the  infiltration  of  fat  and 
glycogen  occurs  in  the  depressed  nerve  cell,  they  would  be 
expected  also  to  occur  in  depressed  cardiac  fibers  and  fatty 
deposits  were  actually  found. 

The  piling  up  of  substance  within  the  fiber  is  a  demonstra- 
tion that  the  metabolism  of  depression  is  relatively  different 
from  that  of  excitation,  which  is  characterized  by  a  diminution 
of  substance.  This  diminution  of  substance  in  the  latter  case 
is  accomplished  by  a  predominance  of  oxidative  or  dissimilative 
processes  over  assimilative  processes.  It  can  be  deduced  that 
the  increase  of  substances  in  the  case  of  depression  is  accom- 
plished by  a  retarding  of  the  oxidative  processes.  First,  be- 
cause depression  was  experimentally  produced  by  creating  as 
complete  an  anoxidative  metabolism  as  possible,  the  hydrogen 
gas  substitution  series.  Second,  because  the  diminution 
or  absence  of  function  which  occurs  in  depression  is  the 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE  233 

manifestation  and  therefore  the  index  of  the  degree  of  the 
dissimilative  phase  of  metabolism.  This  deduction  is  in  accord 
with  Verworn  ('13,  238). 

The  progressive  condensation,  approaching  the  final  stage 
of  hyaline  metamorphosis,  demonstrates  a  metabolism  leading 
to  a  degenerative  state.  Morphologically,  this  is  demonstrated 
by  a  progressive  condensation  of  structures  throughout  the 
process,  indicating  that  the  hyaline  condition  is  gradually 
approached.  It  seems  most  probable,  then,  that  the  factors 
which  condition  the  gradual  condensation  also  condition  the 
hyaline  degenerated  state  if  carried  to  a  sufficient  degree  over 
a  sufficient  period  of  time. 

From  the  nuclear  side,  there  is  evidence  that  the  s tuning  of 
the  nucleus  with  newly  formed  nuclear  material  is  not  without 
katabolic  significance. 

Efficient  metabolism  depends  upon  the  reciprocal  inter- 
change of  nuclear  and  cytoplasmic  substances.  In  depression, 
the  nuclear  material  is  retained  within  the  nucleus  so  that  the 
reciprocal  interchange  is  obviously  impaired.  The  appearance 
of  the  chromatin  in  the  depressed  nucleus  is  not  typical  and 
may  be  due  to  the  incomplete  formation  of  the  substance. 
The  material  is  diffuse  and  is  not  formed  in  discrete  granules 
as  in  the  normal  fiber.  The  condition  might  also  be  interpreted 
as  a  karyolysis  after  having  been  once  completely  formed.  The 
ascribing  of  a  karyolytic  significance  is  further  given  some 
foundation  by  the  observation  of  the  later  nuclear  changes  in 
which  the  nucleus  shrinks  and  becomes  elongated.  Finally, 
not  only  is  the  nuclear  content  diminished  but  also  the  chro- 
matic material  of  the  cross  striations  disappears  completely 
when  depression  reaches  the  state  of  hyaline  change. 

Mechanics  of  anabiosis  in  excitation  following  depression.  — 
The  katabiotic  process  of  depression  is  conditioned  by  a  relative 
asphyxiation  of  the  fiber  because  of  an  incapability  of  using 
oxygen  in  its  metabolism.  Materials  are  stored  in  the  cell  but 
they  are  incompletely  synthesized  because  of  the  impaired 
metabolism.  After  the  restraint  of  depression  is  removed, 
those  substances  which  the  fiber  was  incapable  of  using  can 


234  COLLIER 

now  be  utilized  in,  cell  metabolism.  The  result  is  a  rapid  in- 
crease in  size  of  the  fiber  and  an  increased  functional  capability 
of  the  organ  which  is  a  true  anabiosis. 

Mechanics  of  katabiosis  in  depression  following  excitation. — 
The  observation  that  the  alterations  produced  by  excitation 
persist  and  upon  them  are  placed  the  changes  peculiar  to  de- 
pression demonstrates  the  fact  that  depression  will  not  nullify 
the  changes  produced  by  excitation.  Depression  following  ex- 
citation does  not  bring  the  fiber  back  to  normal  metabiosis  as 
does  the  opposite,  excitation  following  depression.  The  reason 
is  that  depression  introduces  conditions  which  are  abnormal, 
deficient  oxidation,  anoxidative  disintegration  and  storage  of 
unsynthesized  food. 

Analysis  of  the  action  of  stimuli.  —  Each  animal  represented 
in  Table  IV  has  two  sets  of  figures.  The  first  and  invariably 
the  smaller  set  of  figures  represents  the  average  of  twenty-five 
pf  the  most  nearly  metabiotic  fibers  or  if  depression  were  pres- 
ent, of  the  most  depressed  fibers.  The  second  set  represents 
the  average  of  the  most  edematous  fibers.  The  two  exceptions 
to  this  rule  are  Rat  28  of  the  digitalis  series  and  Dog  36  after 
strychnine  in  which  all  of  the  fibers  were  edematous.  The 
functional  state  as  stated  in  the  second  column  is  based  upon 
the  cytological  diagnosis  of  the  fibers  measured.  In  each  in- 
stance this  diagnosis  based  upon  morphology  is  checked  by  the 
nucleus-plasma  coefficient.  The  different  coefficients  obtained 
can  be  arbitrarily  divided  into  three  groups.  The  middle 
group  has  practically  an  identical  coefficient,  that  of  the  meta- 
biotic fiber  which  has  been  definitely  established  for  the  heart 
muscle  fiber  in  the  first  section  (Table  I) .  Table  IV  shows  that 
all  coefficients  with  a  numerical  value  below  that  of  the  meta- 
biotic fiber  are  obtained  from  the  measurement  of  depressed 
cells,  and  all  coefficients  with  a  numerical  value  above  that  of 
the  metabiotic  fiber  are  obtained  from  the  measurement  of 
excited  cells.  Not  only  is  the  numerical  value  of  the  nucleus- 
plasma  coefficient  diagnostic  of  the  states  of  metabiosis,  de- 
pression, or  excitation,  but  it  is  also  a  valuable  index  of  the 
degree  of  excitation  or  depression. 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE 


235 


TABLE  IV.  COMPARATIVE  DATA  OF  MEASUREMENTS  OF  KATABIOTIC 
HEART  FIBERS 


Animal 

Functional 
State 

Cross  sectional  area  of 

Nucleus-plasma  coefficient 

Fiber 

Nucleus 

Depression 

Metabiosis 

Excitation 

RATS 
Digitalis  Series 


29 

Excitation 
Excitation 

187.56 
34I-36 

12.09 
17.99 

.... 

.... 

14-51 
17.97 

28 

Excitation 

420.49 

17-39 

23.17 

10 

Metabiosis 
Excitation 

218.11 
425-32 

17.01 
22.17 

11.82 

18.18 

II 

Depression 
Excitation 

115.67 
222.31 

11.64 
13-95 

8.94 

14.94 

23 

Depression 
Depression 

75-90 
109.98 

11.67 
13-59 

5-54 
7.09 

27 

Depression 
Metabiosis 
Excitation 

131-63 
215.84 
290.86 

12.74 
16.84 
17.61 

9-33 

11.81 

15-52 

Pilocarpine  Series 


I 

Depression 

90.41 

10.51 

7.60 

Depression 

229.00 

19.32 

10.58 

.... 

.... 

2 

Metabiosis 

245.04 

19.21 

.... 

H.75 

.... 

Excitation 

454.31 

24.25 





17-73 

Cocaine  Series 


3 

Excitation 

230.77 

15.22 

14.16 

Excitation 

433-77 

20.00 

.... 

20.68 

5 

Depression 

119.86 

11.41 

9.50 

.... 

Excitation 

214.07 

10.86 

.... 

.... 

18.71 

4 

Depression 

125.37 

12.23 

9-25 

.... 

.... 

Excitation 

187.03 

10.63 

16.59 

236 


COLLIER 
TABLE  IV.  —  Continued 


Animal 

Functional 
State 

Cross  sectional  area  of 

Nucleus-plasma  coefficient 

Fiber 

Nucleus 

Depression 

Metabiosis 

Excitation 

Hydrogen  Gas  Substitution  Series 


16 

Depression 
Excitation 

102.84 
199.44 

14.52 
14-73 

6.08 

12.54 

17 

Depression 
Excitation 

144.84 
179.28 

17.87 
13.29 

7.10 

12.49 

24 

Depression 
Excitation 

123.54 
188.47 

15.18 
14.62 

7.14 

u.88 

25 

Depression 
Excitation 

105.81 
I5I-79 

10.52 
10.81 

8.96 

.... 

13-03 

30 

Metabiosis 
Excitation 

201.55 
424.78 

16.09 
22.93 

.... 

11.52 

17-52 

Heat 


26 

Excitation 
Excitation 

141.27 
233-57 

9-75 
15-51 



.... 

13.16 
14.06 

Shock 

6 

Excitation 
Excitation 

182.55 
320.00 

I3.I9 

15.10 

.... 



12.84 
19.19 

Caffein 

9 

Excitation 
Excitation 

250-75 
333-32 

17-50 
16.24 

13-33 
19-52 

DOGS 
Bacillary  Septicaemia 

M.E.43 

Depression 
Excitation 

183-73 
361.28 

21.27 
19.42 

7.64 

.... 

17.60 

ADAPTIVE   CHANGES   OF  HEART  MUSCLE 
TABLE  IV.  —  Continued 


237 


Animal 

Functional 
State 

Cross  sectional  area  of 

Nucleus-plasma  coefficient 

Fiber 

Nucleus 

Depression 

Metabiosis 

Excitation 

Abnormal  Vagus  Stimulation 


N.3i 

Depression 
Excitation 

221.36 
273-I3 

20.64 
17-75 

9-73 

14-39 

Rabies 


N.37 

Depression 
Excitation 

128.28 
231-13 

15-68 
14.62 

7.18 

.... 

14.80 

Strychnine 


N.36 

Excitation 

216.40 

15-67 

.... 

12.80 

No  portion  of  the  experimental  work  is  more  instructive  and 
furnishes  more  conclusive  evidence  of  the  functional  signifi- 
cance of  these  cytological  changes  than  the  digitalis  series. 
The  whole  range  of  functional  cytomorphosis  was  induced  by 
varying  the  dosage  and  the  period  of  administration  of  this 
one  drug.  It  will  be  made  the  basis  of  discussion  and  the  other 
agencies  will  be  discussed  in  comparison  with  it. 

Rat  29  was  given  the  smallest  dosage  in  the  digitalis  series 
over  a  period  of  three  weeks.  It  showed  edema,  longitudinal 
splitting  of  the  fibers,  and  disintegration  of  the  cross  striations 
and  sarcomeres,  all  of  which  have  been  described  as  adaptive 
changes  characteristic  of  overexcitation.  Because  of  the 
marked  edema  and  a  metabolism  favoring  the  cytoplasm, 
these  changes  are  expressed  mathematically  by  a  shift  in  the 
nucleus-plasma  coefficient  in  favor  of  the  cytoplasm.  The 
edema  was  so  great  that  some  of  the  fibers  showed  vacuoliza- 
tion.  There  were  a  number  of  hyperchromatic  fibers  present 
(first  set,  Rat  29)  but  no  metabiotic  fibers  were  found.  They 
gave  a  nucleus-plasma  coefficient  which  was  twenty-six  per 


238  COLLIER 

cent  greater  than  that  of  the  metabiotic  fiber,  and  were  prin- 
cipally of  the  Hodge  type.  The  fibers  in  the  later  stages  of 
excitation  (second  set)  have  a  nucleus-plasma  coefficient 
which  is  twenty-three  per  cent  greater  than  that  of  the  most 
edematous  fibers  of  the  average  normal  animal. 

Rat  28  was  given  the  same  sized  dosage  over  a  period  of 
four  weeks.  Practically  the  same  changes  were  found  in  this 
animal  as  in  the  animal  not  administered  the  drug  for  as  long 
a  time  (Rat  29),  but  the  degree  of  excitation  was  greater  than 
in  the  latter  case.  The  most  edematous  fibers  had  a  nucleus- 
plasma  coefficient  which  was  sixty  per  cent  greater  than  that 
of  the  most  edematous  fibers  of  the  average  normal  rat.  An- 
other index  of  the  degree  of  excitation  was  expressed  by  the 
preponderance  of  hypochromatic  overexcitated  fibers,  almost 
to  the  exclusion  of  hyper  chroma  tic  less  excitated  fibers. 

An  identical  sequence  of  changes  was  found  in  Rat  26  which 
was  subjected  to  moderate  heat,  in  Rat  6  which  was  suffering 
from  operative  shock,  and  in  Rat  9  which  was  given  caffein. 
While  the  quality  of  the  change  is  identical  in  all  cases,  there 
is  a  quantitative  difference  between  them  which  can  be  roughly 
estimated  by  their  respective  nucleus-plasma  coefficients 
found  in  Table  IV. 

In  the  next  group  in  the  digitalis  series  (Rats  10  and  u),  a 
larger  dose  was  administered  (Table  III).  Rat  10  was  given 
this  dosage  for  ten  days.  The  effect  on  the  cytology  of  the  cell 
was  that  of  a  moderate  excitation  upon  which  was  superimposed 
a  very  slight  depression.  There  were  still  many  metabiotic 
fibers  present.  Rat  n  was  given  the  drug  for  three  times  as 
long  as  Rat  10,  and  showed  a  very  much  more  marked  depres- 
sion superimposed  upon  the  primary  excitation  than  was  found 
in  Rat  10.  The  fibers  were  shrunken  in  cross  sectional  area 
and  the  sarcomeres  were  increased  in  length.  The  nuclei 
showed  an  accumulation  of  chromatin  and  accessory  kary- 
osomes,  both  of  which  are  characterisitics  of  depression.  The 
cytoplasm  showed  the  globulation  of  the  sarcomeres  and  longi- 
tudinal splitting  of  the  fibers,  which  are  characteristic  of  exci- 
tation, but  instead  of  the  vacuolization  and  edema  which  is 
usually  associated  with  this  globulation  and  longitudinal 


ADAPTIVE  CHANGES   OF  HEART  MUSCLE  239 

splitting,  the  sarcoplasm  was  condensed  into  an  almost  hyaline 
staining  substance  which  is  characteristic  of  depression.  Hence, 
the  changes  of  depression  were  found  superimposed  upon  those 
of  excitation.  The  most  hyperchromatic  fibers  had  a  nucleus- 
plasma  coefficient  which  was  twenty-eight  per  cent  less  than 
that  of  the  normal  metabiotic  fiber  and  very  few  edematous 
fibers  could  be  found. 

Rat  23  of  the  digitalis  series  was  given  a  still  greater  dosage, 
sixteen  times  as  large  as  the  first  group  of  the  series  and  four 
times  as  great  as  the  second  group.  The  cytological  changes 
were  those  of  depression  but  even  in  a  greater  degree  than 
found  in  Rat  n.  The  period  of  excitation  had  evidently  been 
shorter  and  the  depression  more  intense.  The  fibers  had 
shrunken  to  less  than  half  the  cross  sectional  area  of  the  aver- 
age normal  fiber  and  the  nucleus-plasma  coefficient  of  the 
hyperchromatic  fibers  was  fifty-one  per  cent  below  that  of  the 
average  normal  metabiotic  fiber.  Its  most  edematous  fibers 
had  a  nucleus-plasma  coefficient  of  a  smaller  value  than  that 
of  the  metabiotic  fibers  of  the  average  normal  animal. 

It  is  demonstrated  by  comparison  of  Rats  10  and  1 1  that  the 
same  dosage  over  a  longer  period  of  time  produces  the  greater 
depression,  a  depression  equal  to  that  induced  by  a  larger  dose 
of  the  drug  (Rat  23).  This  secondary  depression  from  the  con- 
tinued administration  of  the  same  sized  dose  of  the  same  drug 
is  evidently  a  cumulative  effect  which  is  equal  to  the  adminis- 
tration of  a  larger  sized  dose.  The  cocaine  series  further 
demonstrates  this  cumulative  effect. 

Rat  3  was  given  a  dose  of  cocaine  every  twelve  hours  for  a 
day  and  a  half  with  the  result  that  the  heart  showed  marked 
excitation.  Rat  5  was  given  the  same  sized  dose  with  the  same 
interval  between  doses  but  for  a  longer  period  of  time,  two 
days.  It  showed  the  characteristic  changes  of  depression  super- 
imposed upon  those  of  excitation.  Rat  4  was  administered  the 
drug  in  an  identical  manner  but  for  a  still  longer  period  of  time, 
three  days,  with  the  result  that  a  very  marked  depression  was 
superimposed  upon  the  changes  of  excitation.  Consequently, 
a  drug  which  in  single  doses  induces  an  excitation  may  induce 
a  secondary  depression  if  the  drug  is  continued  over  a  sufficient 


240  COLLIER 

period  of  time  or  if  the  doses  are  given  without  a  sufficient 
interval  of  time  between  doses  because  of  the  cumulative  effect. 

The  depressions  induced  by  the  drugs  that  have  been  con- 
sidered so  far  were  secondarily  superimposed  upon  primary 
excitations.  In  an  attempt  to  secure  a  primary  depression 
uncomplicated  by  an  excitation,  oxygen  was  removed  from  the 
animal  chamber  to  a  large  degree  by  replacing  the  air  in  the 
chamber  with  hydrogen  mixed  with  air.  While  a  primary  de- 
pression was  not  fully  accomplished  because  certain  stimuli 
acted  centrally  upon  the  nervous  system  resulting  in  reflex 
excitatory  stimuli  to  the  heart,  as  the  initial  excited  state 
suggests,  the  duration  and  degree  of  the  excitation  were  prac- 
tically negligible. 

Rat  1 6  was  subjected  to  such  oxygen  deprivation  for  three 
hours,  until  the  death  of  the  animal.  It  showed  a  marked  de- 
pression in  many  of  its  fibers.  Rat  17  did  not  receive  such 
severe  treatment  but  was  kept  under  the  experimental  condi- 
tions for  a  longer  period  of  time.  While  the  nucleus-plasma 
coefficient  of  its  fibers  does  not  show  a  much  greater  depression 
than  that  of  Rat  16,  a  much  greater  number  of  fibers  were 
affected  in  the  former  animal.  Rats  24  and  25  were  treated 
similarly  to  Rat  17  but  for  a  period  four  times  as  long.  Both 
rats  showed  some  depression  but  Rat  25  showed  a  much  less 
degree  than  any  of  the  animals  of  this  series  which  have  been 
considered  so  far.  Rat  30  which  was  kept  under  the  experi- 
mental conditions  for  a  period  eight  times  as  long  as  Rats  24 
and  25  showed  very  little  evidence  of  depression.  Many  of  its 
fibers  were  metabiotic  and  most  of  them  were  normal  as  shown 
by  its  nucleus-plasma  coefficient  in  Table  IV.  The  conclusion 
can  be  drawn  from  this  data  that  the  organism  becomes 
adapted  to  a  changed  environment  and  its  metabolism  is 
established  upon  a  new  basis.  While  the  heart  fibers  became 
normal,  the  animal  lost  weight  and  became  progressively  more 
lethargic. 

The  last  animal  of  the  digitalis  series,  Rat  27,  was  given  the 
dose  of  the  drug  which  was  known  to  produce  a  depressant 
affect  and  then  was  given  the  same  drug  in  a  dose  that  was 
known  to  have  an  excitant  affect.  It  was  possible  to  find 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE  24! 

fibers  with  the  changes  characteristic  of  excitation  and  others 
with  those  characteristic  of  depression.  However,  they  did 
not  complicate  one  another  in  the  same  fiber  as  in  the  case  of 
Rats  ii  and  23.  The  two  phases  were  confined  to  separate 
fibers  to  a  surprising  degree.  A  cross-sectional  area  of  the 
ventricle  showed  groups  of  edematous  fibers  interspersed  with 
groups  of  more  deeply  staining  fibers.  The  final  excitation 
phase  predominates  in  the  animal  and  leaves  no  trace  of  a 
former  depression  in  such  fibers  as  are  affected  by  the  excita- 
tion because  the  return  from  depression  is  the  normal  process 
of  recovery  hastened  by  the  stimulation  process.  The  resist- 
ance of  depression,  that  is,  the  inhibition  of  oxidative  proc- 
esses, was  removed  and  the  conditions  of  excitation  hasten 
the  recovery  from  depression  by  accelerating  the  rate  of 
metabolism.  Certain  bundles  are  still  in  depression  because 
the  degree  of  excitation  was  insufficient  to  call  all  the  fibers  into 
play,  which  may  have  been  due  either  to  the  inequality  of  the 
transmission  of  the  stimulus  over  the  muscle  system  or  the 
greater  degree  of  depression  in  different  fibers. 

The  two  animals  of  the  pilocarpine  series  verify  the  observa- 
tion made  upon  Rat  27  that  excitation  upon  depression  is  the 
normal  process  of  recovery  from  depression.  It  is  shown  in 
Table  IV  that  Rat  i  which  was  given  the  drug  for  three  months 
showed  a  frank  depression,  but  Rat  2,  which  was  allowed  to 
recover  for  two  weeks  after  the  same  administration  of  the 
drug  as  in  the  case  of  Rat  i,  showed  a  recovery  from  depres- 
sion. There  was  no  evidence  in  Rat  2  of  its  previous  depressed 
state.  The  hyper  chroma  tic  fibers  of  Rat  2  were  almost  three 
times  as  large  as  the  hyperchromatic  fibers  of  Rat  i,  but  the 
nuclei  did  not  increase  proportionately,  so  that  the  relation  of 
nuclear  increase  to  cytoplasmic  increase  was  two  to  three. 
This  is  evidence  that  the  metabolism  of  the  recovery  from 
depression  favors  the  cytoplasm  similarly  to  the  metabolism  of 
excitation. 

The  dogs,  whether  normals  or  experimentally  changed 
animals,  demonstrate  an  identity  of  reaction  to  stimulation 
regardless  of  the  kind  of  stimulation  but,  as  in  the  rat,  de- 
pendent upon  the  quantitative  degree  of  stimulation.  It 


242  COLLIER 

should  be  stated,  however,  that  the  dog's  heart  was  much  more 
resistant  to  experimental  changes  than  the  rat's.  All  of  the 
normal  control  dogs  and  the  Muscular  Exercise  series  showed 
some  fibers  in  all  stages  of  excitation  with  the  possible  excep- 
tion of  the  final  stages.  They  are  characterized  by  the  identical 
changes  found  in  rats.  Muscular  Exercise  41  and  45,  the  ex- 
perimental controls,  showed  a  slight  depression  with  adaptive 
changes  identical  in  kind  and  degree  with  those  of  a  similar 
degree  of  depression  in  the  rat. 

Muscular  Exercise  43,  Normal  Dog  31,  and  the  Rabies 
Dog  37,  all  showed  the  complex  condition  of  depression  super- 
imposed upon  excitation  in  agreement  with  their  physiological 
state  (see  experimental  data) .  The  physiological  depression  of 
Normal  3 1  was  unsuspected  until  the  anatomical  diagnosis  led 
to  the  investigation  of  his  record  in  the  physiological  labora- 
tory. The  degree  of  previous  excitation  was  greatest  in  Mus- 
cular Exercise  43  and  least  in  Normal  31;  the  greatest  degree 
of  depression  was  found  in  the  Rabies  animal  and  least  in 
Normal  31,  all  of  which  can  be  verified  by  reference  to 
Table  IV. 

Dog  36  which  was  given  strychnine  showed  only  an  early 
excitation  with  longitudinal  splitting  and  globular  degenera- 
tion about  the  nucleus  of  some  of  the  fibers. 

Non-specificity  of  stimuli.  —  The  kinds  of  stimuli  used  have 
been  several  kinds  of  drugs,  namely,  digitalis,  cocaine,  pilo- 
carpine,  strychnine,  and  caffein;  operative  shock;  heat;  tox- 
emia from  both  bacillary  and  rabies  infections;  partial  oxygen 
elimination;  and  excess  muscular  exercise:  yet  the  reactions 
have  been  only  of  two  kinds,  namely,  excitation  or  depression, 
although  they  have  been  usually  complicated  by  one  being 
superimposed  upon  the  other.  Thus,  chemical,  mechanical, 
nervous,  trophic,  and  thermic  stimuli  have  only  two  possible 
ways  of  reacting  upon  the  heart,  namely,  by  excitation  or  by 
depression.  Upon  the  basis  of  cytomorphosis,  the  conception 
of  a  specificity  of  stimuli  affecting  the  heart  must  be  denied 
just  as  Dolley  ('16)  denied  any  such  specificity  for  the  nerve 
cell  and  for  the  liver  cell  ('22).  Therefore,  all  abnormalities  of 


ADAPTIVE   CHANGES   OF  HEART  MUSCLE  243 

heart  muscle  must  be  adaptive  changes  to  excitation,  to  de- 
pression, or  to  one  superimposed  upon  the  other,  and  all  patho- 
logical anatomy  of  the  heart  arising  after  maturity  must  be 
capable  of  analysis  in  terms  of  excitation  and  depression. 

The  pathological  significance  of  the  changes.  —  Many 
changes  which  have  been  described  come  within  the  scope  of 
pathological  anatomy  and,  therefore,  have  especial  significance 
to  the  pathologist.  The  pathological  anatomy  resulting  from 
overexcitation  comprises  those  changes  which  are  associated 
with  normal  physiological  activity  carried  to  a  pathological 
degree.  The  changes  of  depression  belong  to  subnormal  physio- 
logical activity  and  likewise  become  pathological  according  to 
their  degree.  From  the  viewpoint  of  stimulation,  the  changes 
of  excitation,  of  depression,  and  of  depression  superimposed 
upon  excitation  are  consecutive  and  phases  of  an  identical 
quantitative  process.  The  process  is  physiological,  but  the 
end  results  in  its  opposite  degrees  are  both  pathological. 

The  final  state  resulting  from  both  excitation  and  depression 
is  cell  death.  Both  excitation  and  depression  have  one  set  of 
changes  which  are  associated  with  a  rapid  approach  to  cell 
death  and  another  set  of  changes  which  are  associated  with  a 
slow  death.  This  statement  means  that  the  degenerations  and 
necroses,  and  the  necrobioses  and  atrophies  of  the  heart,  are 
referred  to  stimulation. 

Dilatation.  —  Hypertrophy  is  the  state  in  which  the  cell  is 
working  at  its  maximum  efficiency.  This  deduction  may  be 
drawn  because  the  range  of  greatest  efficiency  must  lie  within 
the  metabiotic  cell  and  the  largest  metabiotic  cell  with  the 
largest  amount  of  organized  material  must  be  the  most  func- 
tionally efficient  cell.  From  this  association  of  maximum  effi- 
ciency and  irritability  and  from  the  fact  that  its  sarcomeres 
show  the  greatest  degree  of  tetanic  contraction,  demonstrated 
by  having  the  shortest  length,  it  is  demonstrated  to  be  the  cell 
in  the  greatest  degree  of  tone. 

The  break  in  the  metabiotic  adjustment  of  the  rate  and  in- 
tensity of  stimulation  to  the  metabolism  conditions  a  progres- 
sive loss  of  tonicity.  This  begins  on  the  side  of  excitation  with 


244  COLLIEE 

the  Hodge  cell,  and  on  the  side  of  depression  with  the  shrinkage 
of  the  fiber  and  the  piling  up  of  chromatic  material  within  the 
nucleus.  This  loss  of  tone  is  made  morphologically  evident  by 
the  elongation  of  the  sarcomeres  and  finally  in  both  excitation 
and  depression  by  a  shrinkage  in  the  volume  of  the  sarcomere, 
although  there  is  still  a  progressive  increase  in  length.  Meas- 
urements of  the  depressed  cells  and  of  the  cells  in  the  final 
stage  of  excitation  show  a  fiber  of  greater  length  but  smaller 
cross  sectional  area.  Taking  the  ventricle  as  a  whole,  this  con- 
ditions a  larger  cavity  with  a  thinner  wall.  Such  a  condition 
is  called  dilatation. 

Thus  dilatation  is  an  end  result  of  both  excitation  and  de- 
pression. Examples  of  dilatations  from  depression  are  most 
commonly  those  resulting  from  undernutrition,  such  as  in 
anemia  and  leukemia  and  those  from  toxic  doses  of  most  drugs. 
The  most  striking  examples  of  a  dilatation  from  physiological 
overwork  are  those  of  the  temporary  cardiac  dilatation  of  the 
Marathon  runner  and  of  the  mountain  climber.  Other  ex- 
amples of  an  excitation  dilatation  are  overwork  from  valvular 
deficiencies  and  from  toxic  doses  of  pure  cardiac  excitant 
drugs.  The  most  common  dilatations  which  the  clinician 
meets  are  those  resulting  from  depression  superimposed  upon 
excitation  such  as  occur  in  most  toxic  diseases  of  the  heart. 

For  the  sake  of  completeness,  the  gross  condition  of  the 
heart  from  the  onset  of  the  loss  of  tone  to  the  onset  of  a  recog- 
nizable excitation  dilatation  should  be  mentioned.  From  the 
Hodge  cell  up  to,  but  not  including,  the  end  stage  of  excitation, 
exhaustion,  there  is  a  progressive  loss  of  tone  and  a  progressive 
increase  in  the  cross  sectional  area  of  the  fiber.  This  conditions 
a  thicker  walled  heart  as  well  as  a  greater  increase  in  its  length 
and  volume.  Such  a  condition  is  a  pseudo-hypertrophy  which 
is  a  transition  stage  to  dilatation.  This  transition  through  an 
enlarged  heart  must  occur  in  all  excitation  dilatations  and  a 
striking  example  of  it  is  the  pseudo-hypertrophic  cloudy  swell- 
ing of  infectious  diseases  which  end  in  dilatation. 

Vacuolar  degeneration.  —  The  end  stage  of  the  immediate 
reaction  to  overexcitation  is  not  only  an  elongated  fiber  but  is 


ADAPTIVE   CHANGES   OF   HEART  MUSCLE  245 

also  associated  with  excessive  edema,  the  formation  of  vacuoles, 
and  the  replacement  of  the  cross  striations  and  fibrillae  with 
a  foam-like  structure  which  exemplifies  the  text  book  picture 
of  vacuolar  or  hydropic  degeneration.  It  has  already  been 
pointed  out  that  this  change  is  found  in  many  normally  func- 
tioning animals.  It  passes  unnoticed  in  the  normal  animal  be- 
cause relatively  few  fibers  are  involved.  It  is  only  when  the 
degree  of  excitation  is  so  great  that  a  greater  number  of  fibers 
is  found  in  this  state  that  the  edema  is  recognized  by  giving 
to  it  a  name  which  implies  a  pathological  significance.  The 
process  is  physiological  because  it  is  found  in  normal  animals 
but  it  has  been  carried  by  overstimulation  to  a  pathological 
degree. 

Hyaline  degeneration.  —  On  the  side  of  depression,  the  re- 
gression from  the  metabiotic  state  is  associated  with  a  progres- 
sive loss  of  tone,  a  progressive  deficiency  of  functional  energy 
production  and  of  metabolism.  These  are  made  morphologi- 
cally evident  by  an  increase  in  the  length  of  the  sarcomeres  and 
a  progressive  shrinkage  of  the  cell  and  a  progressive  loss  of  the 
differentiated  substance,  cross  striations  and  fibrillae  as  the 
end  stage,  the  hyaline  state,  is  reached.  This  hyaline,  shrunken 
cell  is  suggestive  of  the  text  book  picture  of  the  so-called 
hyaline  or  waxy  degeneration,  the  Zenker's  degeneration  of 
muscle  fibers.  The  cytoplasm  stains  a  deep  almost  homoge- 
neous red  and  shows  no  evidence  of  cross  striations.  It  seems 
that  this  so-called  hyaline  degeneration  is  simply  the  end  stage 
of  acute  depression  atrophy,  although  its  exact  relationship 
demands  further  investigation. 

Cloudy  swelling.  —  The  adaptive  changes  of  depression 
superimposed  upon  excitation  are  of  importance  because  it  is 
probably  this  combination  of  factors  which  :'s  met  with  more 
often  in  disease  than  either  excitation  or  depression  in  the  pure 
state.  The  excitation  side  of  the  morphological  complex  is  the 
swelling  of  the  fiber,  the  globular  degeneration  of  the  cross 
striations  and  vacuolization  of  the  sarcoplasm,  while  the  de- 
pression side  is  a  condensation  of  the  edematous  sarcoplasm 
into  granules  and  hyperchromatism  followed  by  karyolysis. 


246  COLLIER 

The  swelling  and  granular  appearance  of  the  sarcoplasm,  the 
hyper chromatism  followed  by  karyolysis,  and  the  degeneration 
of  the  cross  striations  and  of  the  fibrillae  are  the  complex  of 
changes  which  are  typical  of  the  text  book  descriptions  of 
cloudy  swelling.  Overexcitation  alone  furnishes  a  very  similar 
picture  which  is  probably  very  often  confused  with  cloudy 
swelling  proper,  but  the  combination  of  the  two  phases  is 
necessary  to  the  typical  state.  The  pathological  term  can  at 
least  be  more  fittingly  applied  to  the  complex  than  to  the 
changes  of  pure  excitation  because  the  factor  of  depression 
which  enters  into  the  complex  is  not  found  in  normal  animals 
and  suggests  a  more  pathological  significance. 

Necrobiosis,  atrophy.  —  The  three  degenerative  states 
which  have  just  been  described,  namely,  vacuolar  degenera- 
tion, hyaline  degeneration  and  cloudy  swelling,  are  respectively 
the  immediate  changes  of  overexcitation,  the  immediate 
changes  of  depression  and  the  immediate  changes  of  depression 
upon  those  of  excitation.  If  the  rate  and  intensity  of  the 
stimuli  are  of  a  less  degree  but  carried  over  a  greater  length  of 
time  the  regressive  processes  are  slower,  the  cytological  changes 
are  less  marked  and  the  process  is  one  of  necrobiosis.  The  late 
stages  of  necrobiosis  are  degrees  of  atrophy.  The  end  state  of 
cytomorphosis  is  thus  shown  to  be  cell  death  regardless  of 
whether  the  adaptation  is  to  overstimulation  or  understimula- 
tion  or  whether  the  process  is  completed  in  a  short  time,  degen- 
eration and  necrosis,  or  whether  the  process  is  extended  over  a 
longer  time,  necrobiosis  and  atrophy. 

In  the  case  of  excitation,  there  is  an  identity  of  the  processes 
of  immediate  cell  degeneration  and  death  and  of  remote  cell 
death,  as  follows.  The  first  stage  of  the  immediate  reaction  is 
a  hypertrophy.  But,  if  the  rate  and  intensity  of  the  stimuli 
are  not  properly  adjusted  to  the  nutritional  state  of  the  fiber, 
this  hypertrophic  state  is  soon  upset  by  the  failure  of  the 
metabolism  to  keep  up  with  the  overexcitation  and  katabolism 
exceeds  anabolism.  This  relative  predominance  of  katabolism 
progressively  becomes  more  prominent  until  it  may  reach  the 
state  of  complete  organic  exhaustion  of  the  specific  structure 


ADAPTIVE  CHANGES   OF  HEART  MUSCLE  247 

of  the  cell,  namely,  the  fibrillae  and  the  cross  stria tions.  At 
this  stage  the  nuclear  materials  are  also  of  such  a  small  amount 
that  the  life  of  the  cell,  which  depends  upon  the  presence  of 
nuclear  as  well  as  cytoplasmic  substances,  is  endangered  and 
the  state  of  cell  death,  necrosis,  is  approximated.  Likewise, 
the  secondary  or  remote  reaction  to  regulated  overstimulation 
leads  to  the  state  of  hypertrophy.  However,  all  text  books 
agree  that  this  state  eventually  gives  down,  the  katabiotic 
processes  exceed  the  anabiotic  processes  and  the  cell  comes  to 
organic  exhaustion,  a  senile  atrophy,  through  the  process  of 
necrobiosis.  The  cells  in  the  process  of  remote  necrobiosis  and 
those  in  the  process  of  immediate  necrosis  differ  morphologi- 
cally only  because  the  swollen  cell  is  full  of  its  waste  products 
which  have  a  high  osmotic  pressure,  while  the  necrobiotic 
process  is  slower  and  the  cells  are  able  to  get  rid  of  such 
waste  products. 

On  the  side  of  depression,  the  immediate  reaction  to  under- 
stimulation  is  shrinkage  of  the  cell  and  then  of  the  nucleus. 
The  process  is  one  of  progressive  anoxidative  and  metamorphic 
metabolism  with  the  end  result  of  hyaline  or  Zenker's  degenera- 
tion, and  fatty  change,  that  is,  with  a  loss  of  the  specialized 
structure  of  the  cell.  Likewise,  with  a  less  intense  degree  of 
depression  acting  continuously  over  a  longer  period  of  time, 
the  progressive  anoxidative  metabolism  through  its  deficient 
synthesis  produces  cell  atrophy  and  eventual  necrosis.  How- 
ever, the  perverted  metabolism  commonly  conditions  frank 
degenerations  in  association  with  atrophy,  such  as  fatty  de- 
generation and  melanin  pigmentation  (Dolley,  '17). 

Intercalated  discs.  —  It  has  been  observed  that  intercalated 
discs  are  found  in  all  animals,  but  are  more  prominent  and  in 
greater  numbers  in  the  complex  of  depression  superimposed 
upon  excitation.  Their  position  is  always  on  Dobie's  line,  but 
they  do  not  always  follow  the  same  line  across  the  entire  fiber. 
Sometimes  they  form  a  stairstep  on  three  or  even  four  different 
lines.  Their  significance  has  been  questioned.  They  are  not 
artifacts,  as  has  been  claimed  by  some,  for  they  serve  as  ana- 
tomical barriers  during  the  life  of  the  fiber.  It  is  demonstrated 


248  COLLIER 

that  the  stimulus  to  construction  is  not  carried  across  these 
discs  in  two  different  ways.  The  first  is  that  on  one  side  is 
usually  found  an  edematous  segment  while  on  the  other  side  is 
a  less  active  or  a  depressed  segment,  that  is,  the  remote  seg- 
ment undergoes  depression  from  disuse.  The  second  is  that 
almost  invariably  the  degree  of  contraction  or  relaxation  dif- 
fers on  the  two  sides  of  the  disc.  Usually,  the  less  active  side 
is  in  relaxation  and  the  edematous  side  is  in  some  degree  of 
contraction. 

Segmentation  and  fragmentation.  —  J.  B.  MacCallum  ('99, 
409)  defines  segmentation  as  either  a  clean  or  a  stairstep  break 
across  the  breadth  of  the  fiber  always  occurring  at  the  cement 
line  between  muscle  segments.  MacCallum's  "cement  lines" 
are  now  more  commonly  known  as  intercalated  discs  which 
have  been  described  above.  He  defines  fragmentation  as  an 
irregular  break  across  the  breadth  of  the  fiber  occurring  at 
some  degenerated  area. 

When  breaks  occur  at  some  point  other  than  on  the  inter- 
calated disc  and  are  not  explained  as  fragmentation  from  de- 
generations, they  are  probably  artifacts.  Some  writers  have 
said  that  all  fragmentations  and  segmentations  are  artifacts 
due  to  a  dull  knife.  It  can  be  said  that  a  dull  knife  will  create 
artifacts  which  are  similar  to  antemortem  segmentation  and 
fragmentation  but  which  differ  from  each  of  them  in  three  re- 
spects. Segmentation  is  differentiated  from  artifacts  in  that, 
first,  they  do  not  show  the  deeply  stained  intercalated  disc 
adhering  to  the  end  of  one  segment;  second,  they  do  not  show 
different  stages  of  contraction  on  the  two  sides  of  the  broken 
fiber,  which  confirms  MacCallum;  and  third,  they  do  not 
show  different  stages  of  excitation  and  depression  on  the  two 
sides  of  the  broken  fiber  as  does  true  antemortem  segmentation. 
Fragmentation  is  differentiated  from  artifacts  in  that,  first, 
antemortem  fragmentation  is  characterized  by  a  wrinkling  and 
retraction  of  the  broken  ends  which  seem  to  indicate  that  the 
break  resulted  from  a  too  great  stretch  of  the  degenerated  fiber 
with  the  result  that  the  fiber  broke  and  the  ends  snapped  apart. 


ADAPTIVE  CHANGES   OF  HEART  MUSCLE  249 

The  second  and  third  characteristics  are  the  same  as  those  of 
segmentation. 

True  fragmentation  has  been  found  to  be  much  more  rare  in 
rat  and  dog  hearts  than  in  the  human  heart.  No  detailed  study 
of  the  human  heart  has  been  made,  but  a  comparison  of  the 
human  heart  with  the  rat  and  dog  heart  was  made  to  find  some 
explanation  for  this  fact.  It  has  been  found  that  degeneration 
in  the  rat  and  dog  hearts  is  principally  in  the  longitudinal 
direction  and  in  the  human  it  is  in  the  transverse  direction. 
This  suggests  that  the  relative  frequency  of  fragmentation  in 
the  human  heart  is  due  to  the  tendency  to  transverse  degenera- 
tion, as  MacCallum  claimed.  This  would  also  explain  the 
relative  infrequency  of  fragmentation  in  the  rat  and  dog  hearts 
which  have  the  tendency  to  longitudinal  instead  of  transverse 
degeneration. 

(In  conclusion,  I  wish  to  acknowledge  that  I  have  consciously  used  the 
work  of  Dr.  D.  H.  Dolley  upon  the  nerve  cell  as  a  criterion  for  this  work 
on  the  heart  muscle.  I  make  this  acknowledgment  because  I  realize 
that  credit  has  probably  not  always  been  given  where  credit  is  due  and 
because  I  realize  that  nothing  has  been  added  to  the  study  of  the  funda- 
mental relation  of  stimulation  to  cytomorphosis  beyond  his  work  on  the 
nerve  cell.  I  also  wish  to  express  my  appreciation  to  Dr.  Dolley  for  his 
personal  direction  of  the  work  and  for  his  valuable  suggestions  and  con- 
structive criticism  which  I  have  received  during  the  writing  of  this 
paper.) 

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ADAPTIVE   CHANGES   OF  HEART  MUSCLE  251 

Tangl  and  Zunst.  1898.  Ueber  die  Einwirkung  der  Muskelarbeit  auf 
den  Blutdruck.  Arch.  f.  d.  gesam.  Physiol.,  Ixx,  544. 

Thoma.  1896.  General  Pathology  and  Pathological  Anatomy.  Trans- 
lated by  Alexander  Bruce.  Adam  and  Chas.  Black,  London,  i,  369. 

Verworn,  Max.  1896.  General  Physiology.  English  Translation  of  2d. 
Edit .  London  ,353. 

1906-7.     Die  Vorgange  in  den  Elementen  des  Nervensystems. 

Zeitsch.  f.  all.  Physiol.,  vi,  Sammelreferate  II. 

1906-7.    Die  Cellularphysiologische  Grundlage  des  Gedachtnisses. 

Zeitsch.  f.  allg.  Physiol.,  vi,  119. 

1913.    Irritability.    Yale  Univ.  Press. 

Virchow.     1858.     Cellular   Pathology.     Translation  of   2d.  Edit,   by 

de  Witt,  N.  Y.,  93. 
Weigert.     1896.     Neue  Fragestellungen  der  pathologischen  Anatomic. 

Deutsch.  Med.  Wochenschrift,  635. 
Zeigler,  E.     1891.    Ursachen  der  pathologischen  Gewebsneubildungen. 

Intern.  Beitr.  f.  Virchow,  ii. 


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VITA 

William  Dean  Collier  was  born  at  Trenton, 
Missouri,  January  15,  1897.  He  was  one  of  three 
children,  the  only  son,  born  to  Weltha  and  the 
late  James  Lewis  Collier.  He  entered  public 
school  at  the  age  of  seven  and  graduated  from 
Trenton  High  School  in  1915. 

In  the  fall -of  1915,  he  entered  the  University 
of  Missouri  and  pursued  the  prerequisite  require- 
ments for  entrance  into  the  School  of  Medicine. 
He  entered  the  School  of  Medicine  in  1917,  and 
was  graduated  from  the  University  in  1919  with 
the  degree  of  Bachelor  of  Arts  and  a  certificate 
of  completion  of  the  first  two  years  in  the  School 
of  Medicine.  He  entered  the  Graduate  School  at 
the  same  institution  and  studied  in  Pathology  un- 
der the  direction  of  Dr.  D.  H.  Dolley.  He  com- 
pleted the  requirements  for  the  degree  of  Master 
of  Arts  in  1920  which  was  formally  conferred  in 
1921. 

During  the  years  '20-'21  and  '21-'22,  he  was 
granted  a  University  Fellowship  in  Pathology. 
These  two  years  were  spent  under  the  directirr 
of  Dr.  D.  H.  Dooley  and  Dr.  George  Lefevre  to 
whom  he  expresses  his  appreciation  for  their  sym- 
pathetic guidance  of  his  studies. 


